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  • 1. Dutta, Suman
    et al.
    Bhaduri, Nipa
    Upadhayaya, Ram Shankar
    Rastogi, Neha
    Chandel, Sunita G.
    Vandavasi, Jaya Kishore
    Plashkevych, Oleksandr
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Kardile, Ramakant A.
    Chattopadhyaya, Jyoti
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    The R-diastereomer of 6 '-O-toluoyl-carba-LNA modification in the core region of siRNA leads to 24-times improved RNA silencing potency against the HIV-1 compared to its S-counterpart2011Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, nr 11, s. 1110-1119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The modified siRNA with pure [6'(S)-O-(p-toluoyl)-7'(S)-methyl]-carba-LNA [6'(S)-O-toluoyl-jcLNA] at position T(13) displayed an IC(50) of 79.8 nM, which has been found to be nearly 24-times less potent as a HIV-1 RNAi silencing agent against TAR RNA than that of the corresponding pure [6'(R)-O-(ptoluoyl)-7'(S)-methyl]jcLNA [6'(R)-O-(p-toluoyl)-jcLNA] counterpart [IC(50) 3.3 nM]. The later [6'(R)-O-(p-toluoyl)-jcLNAl-modified siRNAs have been found to be nearly 2-fold more efficient as a silencing agent than the corresponding 6'-deoxy-jcLNA modified siRNA [IC(50) 8.1 nM], and also nearly 3-fold more effective as a silencing agent than that of LNA-modified siRNA [IC(50) 11.7 nM], thereby showing that the 6'-carbon center in the jcLNA-modified siRNA in the core region is relatively more exposed to the Ago protein in the RISC with a clear chirality preference for the siRNA cleavage reaction. It is noteworthy that the IC(50) of jcLNA-modified siRNAs are very comparable to that of the native siRNA [1.8 nM]. The jcLNA derivatized siRNAs, however, have a clear advantage of being, in general, considerably more stable in human serum. The main structural difference in duplexes of the antisense strand of the 6'(R or S)-O-(p-toluoyl)-jcLNA modified siRNA and target RNA duplex is found to be the spatial orientation of the 6'(R)-O-toluoyl group, which is exposed towards the edge of the duplex backbone, while the 6'(S) makes the minor groove relatively inaccessible for the Ago protein in the RISC. Clearly, any further C6'-modification in jcLNA-modified siRNAs with any hydrophobic group for tighter binding and cleavage or for cross-linking in the core region should preferably be done in the 6'(R)-stereochemistry.

  • 2.
    Gossas, Thomas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Nordström, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Xu, Ming-Hua
    Sun, Zhi-Hua
    Lin, Guo-Qiang
    Wallberg, Hans
    Danielson, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors: characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors2013Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 4, nr 2, s. 432-442Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The kinetic characteristics of hydroxamate-based inhibitors of matrix metalloproteinase (MMP)-12 were explored using an SPR biosensor-based assay and enzyme inhibition analysis. These high-affinity inhibitors were shown to dissociate very slowly from the enzyme-inhibitor complex while a carboxylate analogue had a much faster dissociation rate, verifying the importance of the hydroxamate group for the slow dissociation. Progress curve enzyme inhibition analysis confirmed that the hydroxamate compounds but not the carboxylate compound acted as time-dependent inhibitors. The slow dissociation excluded steady-state estimation of IC50-values and K-i values but also made K-i values from progress curve analysis unreliable. Although a full characterization of the inhibitors using biosensor analysis was limited by slow dissociation, it provided kinetic and mechanistic information of relevance for MMP drug discovery and avoided some pitfalls of conventional enzyme inhibition assays.

  • 3.
    Haglund, Caroline
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mohanty, Chitralekha
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    D'Arcy, Padraig
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Linder, Stig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Identification of an inhibitor of the ubiquitin-proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function2014Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 5, nr 3, s. 376-385Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ubiquitin-proteasome system (UPS) represents one of the most promising therapeutic targets in oncology to emerge in recent years. Here we used a combination of cytotoxic and image-based screening assays to identify a novel UPS inhibitor, designated HRF-3. HRF-3 evokes a gene expression profile similar to that of other characterized ups inhibitors, suggesting a common mechanism of action. Consistent with UPS inhibition, HRF-3 induced strong accumulation of polyubiquitinated proteins in cells. Surprisingly, HRF-3 induced only weak accumulation of two proteasome targeted reporter proteins, Ub(G76V)-YFP and ZsGreen-ODC. Consistent with this observation, HRF-3 did not inhibit proteasome proteolytic activity in an in vitro assay. Similar to a number of other UPS inhibitors, HRF-3 increased the expression of the redox-inducible protein Hmox-1. In distinction to the 20S inhibitor bortezomib, but similarly to two different p97/VCP inhibitors. HRF-3 did not elicit strong induction of the chaperone Hsp70B'. Finally, we show that HRF-3 is cytotoxic to a variety of cancer cell lines and ex vivo patient tumour cells, with the strongest activity observed in cells of leukemic/myeloma origin. Taken together our data show that HRF-3 induces polyubiquitin accumulation in the absence of efficient proteasomal blocking, and suggest that induction of oxidative stress is a common denominator of UPS inhibitors.

  • 4.
    Kulen, Martina
    et al.
    Umea Univ, Dept Chem, S-90187 Umea, Sweden;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.
    Nunez-Otero, Carlos
    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.
    Cairns, Andrew G.
    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.
    Lindgren, Anders E. G.
    Umea Univ, Dept Chem, S-90187 Umea, Sweden;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.
    Wede, Emma
    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.
    Singh, Pardeep
    Umea Univ, Dept Chem, S-90187 Umea, Sweden;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.
    Vielfort, Katarina
    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.
    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.
    Good, James A. D.
    Umea Univ, Dept Chem, S-90187 Umea, Sweden;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergström, 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.
    Gylfe, Åsa
    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.
    Almqvist, Fredrik
    Umea Univ, Dept Chem, S-90187 Umea, Sweden;Umea Univ, Umea Ctr Microbial Res, S-90187 Umea, Sweden.
    Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors2019Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, nr 11, s. 1966-1987Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

  • 5. Lam, V. M.
    et al.
    Rodriguez, D.
    Zhang, T.
    Koh, E. J.
    Carlsson, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salahpour, A.
    Discovery of trace amine-associated receptor 1 ligands by molecular docking screening against a homology model2015Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 6, s. 2216-2223Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Trace Amines (TA) are side-products of the synthesis of classical neurotransmitters within the brain. TAs exert their effect by binding to a family of G protein-coupled receptors termed Trace Amine-Associated Receptors (TAARs). TAAR1 is the best characterised member of this family and studies on TAAR1 have shown that this receptor is a negative regulator of dopamine transmission. Considering the limited number of pharmacological probes available for TAAR1, we aimed to identify novel ligands of this receptor using structure-based virtual screening. A homology model of TAAR1 was generated and over three million commercially available compounds were screened against the orthosteric site using molecular docking. Among the 42 top-ranked compounds that were tested in functional assays, three partial agonists with EC50 values ranging from 1 to 52 [small mu ]M were discovered. In addition, four potentially weak antagonists were identified. Ten analogs of the two most potent agonists from the screen were also evaluated and three of these displayed equal or greater activity compared to the parent compound. Several of the discovered ligands represent novel scaffolds and are thus promising starting points for development of new pharmacological tools for studying TAAR1 biology.

  • 6.
    Llona-Minguez, Sabin
    et al.
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Ghassemian, Artin
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Baranczewski, Pawel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ Drug Optimizat & Pharmaceut Profilin, Uppsala, Sweden..
    Desroses, Matthieu
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Koolmeister, Tobias
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ Drug Optimizat & Pharmaceut Profilin, Uppsala, Sweden.
    Scobie, Martin
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Structure-metabolism-relationships in the microsomal clearance of piperazin-1-ylpyridazines2017Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 8, nr 7, s. 1553-1560Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we provide insight into the metabolic profile of a series of piperazin-1-ylpyridazines suffering from rapid in vitro intrinsic clearance in a metabolic stability assay using liver microsomes (e.g. compound 1 MLM/HLM t(1/2) = 2/3 min). Aided by empirical metabolite identification and computational predictive models, we designed the structural modifications required to improve in vitro intrinsic clearance by more than 50-fold (e.g. compound 29 MLM/HLM t(1/2) = 113/105 min).

  • 7.
    Nordqvist, Anneli
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Mikael T.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Lagerlund, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Muthas, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gising, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Yahiaoui, Samir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Srinivasa, Bachally R.
    Astra Research Center India, Bangalore, India.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mowbray, Sherry L.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors2012Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 3, nr 5, s. 620-626Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.

  • 8.
    Poongavanam, Vasanthanathan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
    Corona, Angela
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
    Steinmann, Casper
    Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.;Aalborg Univ, Dept Chem & Biosci, Aalborg, Denmark..
    Scipione, Luigi
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Grandi, Nicole
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
    Pandolfi, Fabiana
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Di Santo, Roberto
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Costi, Roberta
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Esposito, Francesca
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
    Tramontano, Enzo
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy.;CNR, Ist Ric Genet & Biomed, Monserrato, CA, Italy..
    Kongsted, Jacob
    Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark..
    Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: binding mode insights through magnesium complexation and site-directed mutagenesis studies2018Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 9, nr 3, s. 562-575Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

  • 9. Rodriguez, Anna
    et al.
    Guerrero, Angel
    Gutierrez de Teran, Hugo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Rodriguez, David
    Brea, Jose
    Loza, Maria I.
    Rosell, Gloria
    Bosch, M. Pilar
    New selective A(2A) agonists and A(3) antagonists for human adenosine receptors: synthesis, biological activity and molecular docking studies2015Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 6, nr 6, s. 1178-1185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report the synthesis and pharmacological characterization of a new series of adenosine derivatives on the four adenosine receptors (ARs). In radioligand binding assays, some of the compounds (1, 4, 6 and (R)-6) display a potent affinity for the A(2A)AR (K-i values < 10 nM) with high A(1)/A(2A) and A(2B)/A(2A) selectivity, moderate for the A(3)AR and low for the A(1)AR. The affinity of the epimeric mixture 6 was similar to that of the corresponding (R)-6 stereoisomer and 10-fold higher than that of the (S)-6 stereoisomer. The phenylethylamino group appears to play a key role on the activity, but introduction of groups of different sizes and electronegativity does not induce a substantial change in affinity for the A(2A)AR. In functional assays, most of the compounds produced similar amounts of cAMP compared to NECA, thus behaving as full A(2A)AR agonists. In addition, compounds 1, 2, 3, 5, (S)-6 and 9 resulted to be good antagonists for A(3)AR with K-B in the 6-14 nM range. Docking studies on the A(2A)AR showed a conserved binding mode consistent with previous A(2A)AR agonist-bound crystal structures, allowing for a rational interpretation of the SAR of this compound series.

  • 10.
    Trousil, Sebastian
    et al.
    Imperial College London, UK.
    Carroll, Laurence
    Imperial College London, UK.
    Kalusa, Andrew
    Imperial College London, UK.
    Åberg, Ola
    Imperial College London, UK.
    Kaliszczak, Maciej
    Imperial College London, UK.
    Aboagye, Eric O.
    Imperial College London, UK.
    Design of symmetrical and nonsymmetrical N,N-dimethylaminopyridine derivatives as highly potent choline kinase alpha inhibitors2013Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 4, nr 4, s. 693-696Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Choline kinase alpha is hyperactivated in many solid tumours and regulates malignant progression, making it a promising cancer drug target. The successful design and synthesis of novel inhibitors with high cellular activity are described.

  • 11.
    Wallinder, Charlotta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Sundholm, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Guimond, Marie-Odile
    Univ Sherbrooke, Fac Med & Hlth Sci, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada.
    Yahiaoui, Samir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Gallo-Payet, Nicole
    Univ Sherbrooke, Fac Med & Hlth Sci, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Alterman, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    High affinity rigidified AT(2) receptor ligands with indane scaffolds2019Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, nr 12, s. 2146-2160Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.

  • 12. Yngve, Ulrika
    et al.
    Paulsen, Kim
    Macsari, Istvan
    Sundstrom, Marie
    Santangelo, Ellen
    Linde, Christian
    Bogar, Krisztian
    Lake, Fredrik
    Besidski, Yevgeni
    Malmborg, Jonas
    Stromberg, Kia
    Appelkvist, Paulina
    Radesater, Ann-Cathrine
    Olsson, Fredrik
    Bergstrom, Daniel
    Klintenberg, Rebecka
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Triazolopyrimidinones as gamma-secretase modulators: structure-activity relationship, modulator profile, and in vivo profiling2013Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 4, nr 2, s. 422-431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structure-activity relationship for a series of potent g-secretase modulators based on the 6,7-dihydro4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on A beta processing, as well as in vivo efficacy, for the optimized compounds.

  • 13.
    Öhrngren, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wu, Xiongyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Persson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ekegren, Jenny
    Wallberg, Hans
    Vrang, Lotta
    Rosenquist, Åsa
    Samuelsson, Bertil
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents2011Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, nr 8, s. 701-709Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.

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