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  • 1.
    Al-Amin, Rasel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for Life Laboratory, SciLifeLab, Science for Life Laboratory, SciLifeLab.
    Johansson, Lars
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Blokzijl, Andries
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Dept. Of Immunology, Genetics and Pathology,.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Target Engagement-Mediated Amplification for Monitoring Drug-Target Interactions in SituManuscript (preprint) (Other academic)
    Abstract [en]

    It is important to determine the localization of drugs or drug candidates at cellular and subcellular resolution in relevant clinical specimens. This is necessary to evaluate drug candidates from early stages of drug development to clinical evaluation of mutations potentially causing resistance to targeted therapy. We describe a technology where oligonucleotide-conjugated drug molecules are used to visualize and measure target engagement in situ via rolling-circle amplification (RCA) of circularized oligonucleotide probes (padlock probes). We established this target engagement-mediated amplification (TEMA) technique using kinase inhibitor precursor compounds, and we applied the assay to investigate target interactions by microscopy in pathology tissue sections and using flow cytometry for blood samples from patients, as well as in commercial arrays including almost half of all human proteins.  In the variant proxTEMAtechnique, in situ proximity ligation assays were performed by combining drug-DNA conjugates with antibody-DNA conjugates to specifically reveal drug binding to particular on- or off-targets in pathological tissues sections. In conclusion, the TEMA methods successfully visualize drug-target interaction by experimental and clinically approved kinase inhibitors in situ and with kinases among a large collection of arrayed proteins. 

  • 2.
    Borhade, Sanjay R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Arvidsson, Per I.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties2015In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 10, no 3, p. 455-460Article in journal (Refereed)
    Abstract [en]

    Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

  • 3.
    Caraballo, Remi
    et al.
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden..
    Larsson, Mikael
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Nilsson, Stefan K.
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Ericsson, Madelene
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Qian, Weixing
    Umea Univ, Chem Biol Consortium Sweden, Labs Chem Biol Umea, SE-90187 Umea, Sweden..
    Tran, Nam Phuong Nguyen
    Kindahl, Tomas
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden..
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Saar, Valeria
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Olivecrona, Gunilla
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Enquist, Per-Anders
    Umea Univ, Chem Biol Consortium Sweden, Labs Chem Biol Umea, SE-90187 Umea, Sweden..
    Elofsson, Mikael
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden.;Umea Univ, Chem Biol Consortium Sweden, Labs Chem Biol Umea, SE-90187 Umea, Sweden..
    Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo2015In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, p. 191-209Article in journal (Refereed)
    Abstract [en]

    The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo.

  • 4.
    Fransson, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nordvall, Gunnar
    Bylund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson-Jonsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kratz, Jadel M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues2014In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, ACS medicinal chemistry letters, ISSN 1948-5875, Vol. 5, no 12, p. 1272-1277Article in journal (Refereed)
    Abstract [en]

    The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.

  • 5.
    Fransson, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kratz, Jadel M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Constrained H-Phe-Phe-NH2 Analogues With High Affinity to the Substance P 1-7 Binding Site and With Improved Metabolic Stability and Cell Permeability2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 12, p. 4953-4965Article in journal (Refereed)
    Abstract [en]

    We recently reported the discovery of H-Phe-Phe-NH2 as a small and high affinity ligand for the substance P 1-7 (SP1-7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP1-7 mimetics, the dipeptide was chosen as a lead compound. Herein the structure-activity relationship (SAR) of a set of modified H-Phe-Phe-NH2 analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C-terminal of H-Phe-Phe-NH2 resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability.

  • 6. Gad, Helge
    et al.
    Koolmeister, Tobias
    Jemth, Ann-Sofie
    Eshtad, Saeed
    Jacques, Sylvain A.
    Strom, Cecilia E.
    Svensson, Linda M.
    Schultz, Niklas
    Lundback, Thomas
    Einarsdottir, Berglind Osk
    Saleh, Aljona
    Gokturk, Camilla
    Baranczewski, Pawel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berntsson, Ronnie P. -A.
    Gustafsson, Robert
    Stromberg, Kia
    Sanjiv, Kumar
    Jacques-Cordonnier, Marie-Caroline
    Desroses, Matthieu
    Gustavsson, Anna-Lena
    Olofsson, Roger
    Johansson, Fredrik
    Homan, Evert J.
    Loseva, Olga
    Brautigam, Lars
    Johansson, Lars
    Hoglund, Andreas
    Hagenkort, Anna
    Pham, Therese
    Altun, Mikael
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Vikingsson, Svante
    Evers, Bastiaan
    Henriksson, Martin
    Vallin, Karl S. A.
    Wallner, Olov A.
    Hammarstrom, Lars G. J.
    Wiita, Elisee
    Almlof, Ingrid
    Kalderen, Christina
    Axelsson, Hanna
    Djureinovic, Tatjana
    Puigvert, Jordi Carreras
    Haggblad, Maria
    Jeppsson, Fredrik
    Martens, Ulf
    Lundin, Cecilia
    Lundgren, Bo
    Granelli, Ingrid
    Jensen, Annika Jenmalm
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nilsson, Jonas A.
    Stenmark, Pal
    Scobie, Martin
    Berglund, Ulrika Warpman
    Helleday, Thomas
    MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7495, p. 215-221Article in journal (Refereed)
    Abstract [en]

    Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

  • 7.
    Gising, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Belfrage, Anna Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ehrenberg, Angelica
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Anders, Karlén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielsson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, p. 1790-1801Article in journal (Refereed)
    Abstract [en]

    Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

  • 8.
    Good, James A. D.
    et al.
    Umea Univ, Dept Chem, S-90187 Umea, Sweden.;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden..
    Silver, Jim
    Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden.;Umea Univ, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden..
    Nunez-Otero, Carlos
    Umea Univ, Dept Clin Microbiol, S-90185 Umea, Sweden..
    Bahnan, Wael
    Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden.;Umea Univ, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden..
    Krishnan, K. Syam
    Umea Univ, Dept Chem, S-90187 Umea, Sweden.;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Mannam Mem NSS Coll, Dept Chem, Kollam 691571, Kerala, India..
    Salin, Olli
    Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Umea Univ, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden.;Umea Univ, Dept Clin Microbiol, S-90185 Umea, Sweden..
    Engström, Patrik
    Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden.;Umea Univ, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden.;Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA..
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gylfe, Asa
    Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Umea Univ, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden.;Umea Univ, Dept Clin Microbiol, S-90185 Umea, Sweden..
    Bergstrom, Sven
    Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.;Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden.;Umea Univ, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden..
    Almqvist, Fredrik
    Umea Univ, Dept Chem, S-90187 Umea, Sweden.;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden..
    Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, p. 2094-2108Article in journal (Refereed)
    Abstract [en]

    The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 <= 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 mu M. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

  • 9.
    Islam, Md. Koushikul
    et al.
    Umea Univ, Dept Clin Microbiol, Infect Dis, Umea, Sweden..
    Strand, Mårten
    Umea Univ, Dept Clin Microbiol, Virol, Umea, Sweden..
    Saleeb, Michael
    Umea Univ, Dept Chem, Umea, Sweden..
    Svensson, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Baranczewski, Pawel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wadell, Göran
    Umea Univ, Dept Clin Microbiol, Virol, Umea, Sweden..
    Ahlm, Clas
    Umea Univ, Dept Clin Microbiol, Infect Dis, Umea, Sweden..
    Elofsson, Mikael
    Umea Univ, Dept Chem, Umea, Sweden..
    Evander, Magnus
    Umea Univ, Dept Clin Microbiol, Virol, Umea, Sweden..
    Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 1925Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

  • 10.
    Karlgren, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ahlin, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Palm, Johan
    AstraZeneca R&D, Mölndal, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, p. 411-426Article in journal (Other academic)
    Abstract [en]

    To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter. The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways. Sixty-five compounds were identified as OATP1B1 inhibitors at 20 mu M. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified. Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

  • 11. Kitambi, Satish Srinivas
    et al.
    Toledo, Enrique M.
    Usoskin, Dmitry
    Wee, Shimei
    Harisankar, Aditya
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sigmundsson, Kristmundur
    Kalderen, Christina
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Soumi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Aranda, Sergi
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Andang, Michael
    Damberg, Peter
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arenas, Ernest
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Walfridsson, Julian
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hammarstrom, Lars G. J.
    Ernfors, Patrik
    Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 157, no 2, p. 313-328Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.

  • 12.
    Ladds, Marcus J. G. W.
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Pastor-Fernandez, Andres
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Popova, Gergana
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    van Leeuwen, Ingeborg M. M.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Eng, Kai Er
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Drummond, Catherine J.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Johansson, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol Consortium Sweden, Div Translat Med & Chem Biol,Sci Life Lab, Stockholm, Sweden.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Westwood, Nicholas J.
    Univ St Andrews, Sch Chem & Biomed Sci, Res Complex, St Andrews, Fife, Scotland;EaStCHEM, Res Complex, St Andrews, Fife, Scotland.
    McCarthy, Anna R.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Tholander, Fredrik
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Popa, Mihaela
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Lane, David P.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    McCormack, Emmet
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Internal Med, Hematol Sect, Bergen, Norway.
    McInerney, Gerald M.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Bhatia, Ravi
    Univ Alabama Birmingham, Dept Hematol & Oncol, Birmingham, AL USA.
    Lain, Sonia
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195956Article in journal (Refereed)
    Abstract [en]

    Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.

  • 13.
    Ladds, Marcus J. G. W.
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    van Leeuwen, Ingeborg M. M.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Drummond, Catherine J.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Chu, Su
    Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA..
    Healy, Alan R.
    Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland..
    Popova, Gergana
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Fernandez, Andres Pastor
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Mollick, Tanzina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Darekar, Suhas
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Sedimbi, Saikiran K.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Nekulova, Marta
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic..
    Sachweh, Marijke C. C.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Campbell, Johanna
    Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland..
    Higgins, Maureen
    Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland..
    Tuck, Chloe
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Popa, Mihaela
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Safont, Mireia Mayoral
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Gelebart, Pascal
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Fandalyuk, Zinayida
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Thompson, Alastair M.
    Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Holcombe Blvd, Houston, TX 77030 USA..
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustavsson, Anna-Lena
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17121 Stockholm, Sweden..
    Johansson, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17121 Stockholm, Sweden..
    Farnegardh, Katarina
    Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden..
    Yngve, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Saleh, Aljona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haraldsson, Martin
    Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden..
    D'Hollander, Agathe C. A.
    Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland..
    Franco, Marcela
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Zhao, Yan
    Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England..
    Hakansson, Maria
    SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden..
    Walse, Bjorn
    SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden..
    Larsson, Karin
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Peat, Emma M.
    Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland..
    Pelechano, Vicent
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Lunec, John
    Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England..
    Vojtesek, Borivoj
    Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic..
    Carmena, Mar
    Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland..
    Earnshaw, William C.
    Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland..
    McCarthy, Anna R.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Westwood, Nicholas J.
    Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland..
    Arsenian-Henriksson, Marie
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Lane, David P.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Bhatia, Ravi
    Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA..
    McCormack, Emmet
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.;Haukeland Hosp, Haematol Sect, Dept Med, Bergen, Norway..
    Lain, Sonia
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1107Article in journal (Refereed)
    Abstract [en]

    The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

  • 14.
    Lampa, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ehrenberg, Angelica E.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Danielson, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles2014In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, no 23, p. 6595-6615Article in journal (Refereed)
    Abstract [en]

    With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.

  • 15.
    Lampa, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svahn Gustafsson, Sofia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Danielsson, Helena U.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region2014In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 3, p. 249-254Article in journal (Refereed)
    Abstract [en]

    Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

  • 16.
    Llona-Minguez, Sabin
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Höglund, Andreas
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden.;Sprint BioSci AB, Huddinge, Sweden..
    Jacques, Sylvain A.
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden.;Univ Strasbourg, Fac Pharm, MEDALIS Drug Discovery Ctr, LFCS,CAMB,UMR7199,CNRS,LIT,UMR7200, F-67401 Illkirch Graffenstaden, France..
    Johanson, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden, Stockholm, Sweden..
    Calderon-Montano, Jose Manuel
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Claesson, Magnus
    Stockholm Univ, Dept Biochem & Biophys, Svante Arrhenius Vag 16C, SE-10691 Stockholm, Sweden..
    Loseva, Olga
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Valerie, Nicholas C. K.
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Lundback, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden, Stockholm, Sweden..
    Piedrafita, Javier
    Torrey Pines Inst Mol Studies, 3550 Gen Atom Court, San Diego, CA 92121 USA..
    Maga, Giovanni
    CNR, IGM, Via Abbiategrasso 207, I-27100 Pavia, Italy..
    Crespan, Emmanuele
    CNR, IGM, Via Abbiategrasso 207, I-27100 Pavia, Italy..
    Meijer, Laurent
    ManRos Therapeut, Perharidy Res Ctr, F-29680 Roscoff, Bretagne, France..
    Moron, Estefania Burgos
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Baranczewski, Pawel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Hagbjörk, Ann-Louise
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wiita, Elisee
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Almlof, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Visnes, Torkild
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Jeppsson, Fredrik
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Sigmundsson, Kristmundur
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden, Stockholm, Sweden.;Duke NUS Grad Med Sch, Singapore, Singapore..
    Jensen, Annika Jenmalm
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden, Stockholm, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jemth, Ann-Sofie
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Stenmark, Pal
    Stockholm Univ, Dept Biochem & Biophys, Svante Arrhenius Vag 16C, SE-10691 Stockholm, Sweden..
    Berglund, Ulrika Warpman
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Scobie, Martin
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Helleday, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden..
    Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 12016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 3, p. 1140-1148Article in journal (Refereed)
    Abstract [en]

    The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell sternness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.

  • 17. Over, Bjorn
    et al.
    McCarren, Patrick
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Foley, Michael
    Giordanetto, Fabrizio
    Gronberg, Gunnar
    Hilgendorf, Constanze
    Lee, Maurice D.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Muncipinto, Giovanni
    Pellisson, Melanie
    Perry, Matthew W. D.
    Svensson, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Duvall, Jeremy R.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 6, p. 2746-2754Article in journal (Refereed)
    Abstract [en]

    Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pK(a), and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH -> NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.

  • 18. Prieto, P.
    et al.
    Kinsner-Ovaskainen, A.
    Stanzel, S.
    Albella, B.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Campillo, N.
    Cecchelli, R.
    Cerrato, L.
    Diaz, L.
    Di Consiglio, E.
    Guerra, A.
    Gombau, L.
    Herrera, G.
    Honegger, P.
    Landry, C.
    O'Connor, J. E.
    Paez, J. A.
    Quintas, G.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Turco, L.
    Zurich, M. G.
    Zurbano, M. J.
    Kopp-Schneider, A.
    The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: Results from the European Project ACuteTox2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 4, p. 1357-1376Article in journal (Refereed)
    Abstract [en]

    ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6 months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies. In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50 > 2000 mg/kg b.w.).

  • 19.
    Skogh, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lesniak, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, p. 533-540, article id S0928-0987(17)30497-9Article in journal (Refereed)
    Abstract [en]

    Substance P 1-7 (SP1-7, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP1-7 amide 1 (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-NH2) was previously shown to be superior to the endogenous SP1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys3]SP1-7 amide (3) and the [MeGln5]SP1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg1 and C-terminal Phe7, anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP1-7 amide (1), the [MeLys3]SP1-7 amide (3) amide and the [MeGln5]SP1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain.

  • 20.
    Skogh, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lesniak, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gaugaz, Fabienne Z.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 106, p. 345-351Article in journal (Refereed)
    Abstract [en]

    The heptapeptide SP1-7 (1, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg(1)-Pro(2)-Lys(3)-Pro(4)-GIn(5)-Gln(6)-Phe(7)-Phe(8)-Gly(9)-Leu(10)-Meti(11)-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)-NH2 ) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg(1) in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys(3) of 2 is less important. A displacement with Ala(1) or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t(1/2) = 11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t(1/2) = 6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced antiallodynic effects.

  • 21.
    Skogh, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lesniak, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Diwakarla, Shanti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jonsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice2018In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 14, p. 2446-2450Article in journal (Refereed)
    Abstract [en]

    The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.

  • 22.
    Spahiu, Linda
    et al.
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden..
    Alander, Johan
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden..
    Ottosson-Wadlund, Astrid
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden..
    Svensson, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lehmer, Carina
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden..
    Armstrong, Richard N.
    Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA.;Vanderbilt Univ, Sch Med, Dept Chem, Nashville, TN 37232 USA..
    Morgenstern, Ralf
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden..
    Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 24, p. 3089-3098Article in journal (Refereed)
    Abstract [en]

    Microsomal glutathione transferase 1 (MGST1) has a unique ability to be activated, <= 30-fold, by modification with sulfhydryl reagents. MGST1 exhibits one-third-of-the-sites reactivity toward glutathione and hence heterogeneous binding to different active sites in the homotrimer. Limited turnover stopped-flow kinetic measurements of the activated enzyme allowed us to more accurately determine the KD for the "third" low-affinity GSH binding site (1.4 +/- 0.3 mM). The rate of thiolate formation, k(2) (0.77 +/- 0.06 s(-1)), relevant to turnover, could also be determined. By deriving the steadystate rate equation for a random sequential mechanism for MGST1, we can predict K-M, k(cat), and k(cat)/K-M values from these and previously determined pre-steady-state rate constants (all determined at 5 C). To assess whether the pre-steady-state behavior can account for the steady-state kinetic behavior, we have determined experimental values for kinetic parameters at 5 degrees C. For reactive substrates and the activated enzyme, data for the microscopic steps account for the global mechanism of MGST1. For the unactivated enzyme and more reactive electrophilic substrates, pre steady -state and steady-state data can be reconciled only if a more active subpopulation of MGST1 is assumed. We suggest that unactivated MGST1 can be partially activated in its unmodified form. The existence of an activated subpopulation (approximately 10%) could be demonstrated in limited turnover experiments. We therefore suggest that MSGT1 displays a preexisting dynamic equilibrium between high- and low-activity forms.

  • 23.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors.2017In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374Article in journal (Refereed)
  • 24.
    Tehler, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fagerberg, Jonas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergstrom, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Optimizing Solubility and Permeability of a Biopharmaceutics Classification System (BCS) Class 4 Antibiotic Drug Using Lipophilic Fragments Disturbing the Crystal Lattice2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 6, p. 2690-2694Article in journal (Refereed)
    Abstract [en]

    Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.

  • 25. Vodnala, Suman K.
    et al.
    Lundback, Thomas
    Sjoberg, Birger
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rottenberg, Martin E.
    Hammarstrom, Lars G. J.
    In Vitro and In Vivo Activities of 2-Aminopyrazines and 2-Aminopyridines in Experimental Models of Human African Trypanosomiasis2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 2, p. 1012-1018Article in journal (Refereed)
    Abstract [en]

    New drugs for the treatment of human African trypanosomiasis are urgently needed. A number of 2-aminopyrazines/2-aminopyridines were identified as promising leads following a focused screen of 5,500 compounds for Trypanosoma brucei subsp. brucei viability. Described compounds are trypanotoxic in the submicromolar range and show comparably low cytotoxicity on representative mammalian cell lines. Specifically, 6-([6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)]oxy)-N-(piperidin-4-yl)pyrazin-2-amine (CBK201352) is trypanotoxic for T. brucei subsp. brucei, T. brucei subsp. gambiense, and T. brucei subsp. rhodesiense and is nontoxic to mammalian cell lines, and in vitro preclinical assays predict promising pharmacokinetic parameters. Mice inoculated intraperitoneally (i.p.) with 25 mg/kg CBK201352 twice daily for 10 days, starting on the day of infection with T. brucei subsp. brucei, show complete clearance of parasites for more than 90 days. Thus, CBK201352 and related analogs are promising leads for the development of novel treatments for human African trypanosomiasis.

  • 26. Vodnala, Suman K.
    et al.
    Lundback, Thomas
    Yeheskieli, Esther
    Sjoberg, Birger
    Gustavsson, Anna-Lena
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Olivera, Gabriela C.
    Eze, Anthonius A.
    de Koning, Harry P.
    Hammarstrom, Lars G. J.
    Rottenberg, Martin E.
    Structure-Activity Relationships of Synthetic Cordycepin Analogues as Experimental Therapeutics for African Trypanosomiasis2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 24, p. 9861-9873Article in journal (Refereed)
    Abstract [en]

    Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, la) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic,degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an, oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons. for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics.

1 - 26 of 26
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