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  • 351.
    Åkerbladh, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Palladium-Catalyzed Molybdenum Hexacarbonyl-Mediated Gas-Free Carbonylative Reactions2019In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 2, p. 141-155Article in journal (Refereed)
    Abstract [en]

    This account summarizes Pd(0)-catalyzed Mo(CO) 6-mediated gas-free carbonylative reactions published in the period October 2011 to May 2018. Presented reactions include inter-and intramolecular carbonylations, carbonylative cross-couplings, and carbonylative multicomponent reactions using Mo(CO) 6 as a solid source of CO. The presented methodologies were developed mainly for small-scale applications, avoiding the problematic use of gaseous CO in a standard laboratory. In most cases, the reported Mo(CO) 6-mediated carbonylations were conducted in sealed vials or by using two-chamber solutions. 1 Introduction 2 Recent Developments 2.1 New CO Sources 2.2 Two-Chamber System for ex Situ CO Generation 2.3 Multicomponent Carbonylations 3 Carbonylations with N and O Nucleophiles 4 Carbonylative Cross-Coupling Reactions with Organometallics 5 Carbonylative Cascade Reactions 6 Carbonylative Cascade, Multistep Reactions 7 Summary and Outlook

  • 352.
    Åleskog, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Application of In Vitro Chemosensitivity Testing for Evaluation of New Cytotoxic Drugs in Chronic Lymphocytic Leukaemia2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Despite major advances in the understanding of the biology of chronic lymphocytic leukaemia (CLL), progress in improving its treatment has been limited and it still remains an incurable disorder. In the present research, we have performed in vitro drug sensitivity testing of primary CLL cells for preclinical evaluation of cytotoxic drugs, using the fluorometric microculture cytotoxicity assay (FMCA).

    The tumour type-specific activities of 14 standard drugs, evaluated in vitro on tumour cells from patients with CLL and acute leukaemias, were in good agreement with their known clinical activities. A correlation between drug treatment and development of cellular drug resistance was demonstrated in CLL, but not in the acute leukaemias. Moreover, the nucleoside analogues fludarabine, cladribine, cytarabine and gemcitabine, as well as the anthracycline idarubicin, were highly active in CLL cells.

    A new cytotoxic drug candidate, CHS 828, was evaluated in primary cell cultures from a broad spectrum of tumours. CHS 828 was highly active against haematological malignancies in vitro, especially CLL, but also against some solid tumours. The drug appeared to be non cross-resistant with standard drugs.

    In addition, the relationship between drug sensitivity in vitro and a recently described prognostic factor in CLL, the mutational status of the immunoglobulin variable heavy chain (IgVH) gene, was evaluated. Interestingly, cells with unmutated IgVH genes were more chemosensitive than the mutated cells.

    In summary, our results indicate that in vitro studies on tumour cellsfrom leukaemia patients may yield considerable information regarding the activity, mechanisms of action and cross-resistance of cytotoxic drugs, as well as concerning the relationship between drug sensitivity and prognostic factors, which can be useful in the preclinical evaluation of new cytotoxic drugs. Furthermore, the results suggest that the pyrimidine analogues cytarabine and gemcitabine, as well as the anthracycline idarubicin, may have a role in the treatment of CLL. The new cyanoguanidine CHS 828 is highly active in CLL cells and appears to be non cross-resistant with standard drugs. The poorer prognosis in patients with CLL cells with unmutated IgVH genes can not be explained by increased chemoresistance.

  • 353.
    Öhrngren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Tertiary Alcohol- or β-Hydroxy γ-Lactam-Based HIV-1 Protease Inhibitors: Microwave Applications in Batch and Continuous Flow Organic Synthesis2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the outbreak of the HIV/AIDS pandemic in the 1980s, the disease has cost the lives of over 30 million people, and a further 33 million are currently living with the HIV infection. With the appropriate treatment, HIV/AIDS can today be regarded as a chronic but manageable disease. However, treatment is not available globally and UNAIDS still estimates that there are currently 5000 AIDS-related deaths worldwide per day.

    HIV protease inhibitors (PIs) constitute one of the fundaments of HIV treatment, and are commonly used in so-called highly active antiretroviral therapy (HAART), together with reverse transcriptase inhibitors. Although there are ten PIs on the market, there is still a need for novel structures. The rapid development of resistant strains, due to the high frequency of mutations, together with the commonly observed adverse effects of the drugs available, illustrate the need to develop new potent structures.

    Two novel scaffolds were investigated in this work. A tertiary alcohol-containing scaffold comprising a three-carbon tether, and a β-hydroxy γ-lactam-based scaffold were designed, synthesized and evaluated using enzyme- and cell-based assays. X-ray analyses of inhibitors from each class provided information on inhibitor–protease interactions. The inhibitors containing the tertiary alcohol provided at best an enzymatic inhibition (Ki) of 2.3 nM, and an inhibition in the cell-based assay (EC50) of 0.17 µM. The γ-lactam-based inhibitors exhibited better inhibition than the first series; the best values being Ki = 0.7 nM and EC50 = 0.04 µM.

    The second part of these studies involved the evaluation of a novel non-resonance continuous-flow microwave instrument. The instrument was validated regarding heating capacity, temperature stability and temperature homogeneity. A number of model reactions were performed with low- and high-microwave-absorbing solvents. It was found that the microwave heating source allowed rapid temperature adjustment, together with easily regulated, flow-dependent reaction times, providing an efficient tool for reaction optimisation.

    List of papers
    1. Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
    Open this publication in new window or tab >>Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
    Show others...
    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 4, p. 1053-1057Article in journal (Refereed) Published
    Abstract [en]

    A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102908 (URN)10.1021/jm070680h (DOI)000253353800037 ()18215014 (PubMedID)
    Available from: 2009-05-12 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
    2. Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
    Open this publication in new window or tab >>Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
    Show others...
    2011 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, no 8, p. 701-709Article in journal (Refereed) Published
    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.

    Keywords
    HIV, protease, inhibitor
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-135157 (URN)10.1039/c1md00077b (DOI)000295068100003 ()
    Available from: 2010-12-06 Created: 2010-12-06 Last updated: 2018-01-12Bibliographically approved
    3. Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Open this publication in new window or tab >>Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Show others...
    2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, p. 2724-2736Article in journal (Refereed) Published
    Abstract [en]

    In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

    Keywords
    HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-160186 (URN)10.1021/jm201620t (DOI)000301767000017 ()
    Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2018-01-12Bibliographically approved
    4. Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
    Open this publication in new window or tab >>Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
    Show others...
    2012 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, no 5, p. 1053-1063Article in journal (Refereed) Published
    Abstract [en]

    The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20 degrees C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm X (sic) 3 mm tubular borosilicate reactor and a flow between 47 and 2120 mu L/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels-Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.

    Keywords
    non-resonant, microwave, Continuous-Flow, MAOS, CF-MAOS
    National Category
    Medicinal Chemistry Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-160187 (URN)10.1021/op300003b (DOI)000304129100036 ()
    Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2018-01-12Bibliographically approved
  • 354.
    Öhrngren, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fardost, Ashkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Russo, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fagrell, Magnus
    WaveCraft AB.
    Schanche, Jon-Sverre
    WaveCraft AB.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications2012In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, no 5, p. 1053-1063Article in journal (Refereed)
    Abstract [en]

    The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20 degrees C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm X (sic) 3 mm tubular borosilicate reactor and a flow between 47 and 2120 mu L/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels-Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.

  • 355.
    Öhrngren, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wu, Xiongyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Persson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Ekegren, Jenny
    Wallberg, Hans
    Vrang, Lotta
    Rosenquist, Åsa
    Samuelsson, Bertil
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents2011In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, no 8, p. 701-709Article in journal (Refereed)
    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.

  • 356.
    Örtqvist, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    On the Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: From Tripeptides to Achiral Compounds2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Infection by the hepatitis C virus (HCV) leads to inflammation of the liver, i.e. hepatitis. The acute infection often progresses to a chronic phase during which the liver function is gradually impaired. Approximately 20% of these chronic cases develop liver cirrhosis, with an ensuing increased risk of liver cancer. Global estimates of the total number of chronic cases range from 123–170 million. Yet, neither specific anti-HCV drugs nor vaccines are available. When drugs become available for daily clinical use, rapid development of drug-resistant strains is expected, making resistance an important issue.

    One of the most studied targets for specific anti-HCV drugs is the NS3 protease. The main objectives of the work presented in this thesis were to design and synthesise peptidomimetic inhibitors of this enzyme, and to establish the structure–activity relationships (SARs) regarding the inhibition of the wild type as well as of the known resistant variants A156T and D168V.

    Substituted prolines are common P2 residues in HCV NS3 protease inhibitors. To decrease the peptide character of the inhibitors, the non-coded phenylglycine was evaluated as a proline replacement in combination with known and novel P3 and P1 residues and P2 substituents. The results confirmed that phenylglycine is a promising P2 scaffold, with a possible π-stacking interaction with histidine 57 of the active site. However, to benefit from its full potential, additional optimisation is required.

    A 2(1H)-pyrazinone-based scaffold was introduced as P3 residue. Utilising the scope of the method developed for the pyrazinone scaffold synthesis, the phenylglycine side-chain was transferred to the scaffold. In combination with an aromatic P1 building-block, this design yielded achiral, peptidomimetic inhibitors, three times more potent than the tripeptide lead.

    The SARs for the inhibition of the resistant variants A156T and D168V were investigated for compounds based on either P2 proline or phenyl­glycine. It was concluded that the vulnerability of the inhibitors to alterations in the enzyme depends on the P2 and the P1 residue, not only on the P2 as previously suggested.

    These results provide important information for the design of a new generation of inhibitors with improved properties.

    List of papers
    1.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    2. Structure-Activity Relationships of HCV NS3 Protease Inhibitors Evaluated on the Drug-Resistant Variants A156T and D168V
    Open this publication in new window or tab >>Structure-Activity Relationships of HCV NS3 Protease Inhibitors Evaluated on the Drug-Resistant Variants A156T and D168V
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-111363 (URN)
    Available from: 2009-12-16 Created: 2009-12-11 Last updated: 2018-01-12
    3. A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
    Open this publication in new window or tab >>A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
    2009 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 7, no 13, p. 2809-2815Article in journal (Refereed) Published
    Abstract [en]

    A rapid and versatile one-pot, 2 * 10 min microwave protocol for the prepn. of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones, e.g., I, from the corresponding primary amines and aldehyde was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha -aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta -strand inducing core structures in a medicinal chem. context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-contg. Hepatitis C virus NS3 protease inhibitors, e.g., II, is reported.

    National Category
    Pharmaceutical Sciences
    Research subject
    Medicinal Chemistry; Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-110737 (URN)10.1039/b90550lk (DOI)000267124300020 ()
    Note

    CAN 151:245625 28-17 Heterocyclic Compounds (More Than One Hetero Atom) Journal 1477-0520 written in English. 1178896-10-0P; 1178896-11-1P Role: PAC (Pharmacological activity), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (prepn. and hepatitis C virus NS3 protease inhibitory activity of (pyrazinylacetamido)cyclopropanoic acid derivs. via coupling reaction, hydrolysis, and peptide coupling of pyrazinylacetate deriv.); 4248-19-5 (tert-Butyl carbamate); 259214-56-7 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. and hepatitis C virus NS3 protease inhibitory activity of (pyrazinylacetamido)cyclopropanoic acid derivs. via coupling reaction, hydrolysis, and peptide coupling of pyrazinylacetate deriv.); 1178896-08-6P; 1178896-09-7P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and hepatitis C virus NS3 protease inhibitory activity of (pyrazinylacetamido)cyclopropanoic acid derivs. via coupling reaction, hydrolysis, and peptide coupling of pyrazinylacetate deriv.); 62-53-3 (Aniline); 100-46-9 (Benzylamine); 100-52-7 (Benzaldehyde); 108-91-8 (Cyclohexylamine); 109-73-9 (1-Butanamine); 122-78-1 (Benzeneacetaldehyde); 1122-91-4 (4-Bromobenzaldehyde); 2393-23-9 (4-Methoxybenzylamine); 2462-31-9; 3009-97-0; 3010-04-6; 3081-24-1; 3132-99-8 (3-Bromobenzaldehyde); 3182-93-2; 21760-98-5; 37760-98-8 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. of dichloropyrazinones via Strecker reaction of primary amines, aldehydes, and trimethylsilyl cyanide, followed by cyclocondensation with oxalyl chloride under microwave irradn.); 2182-39-0P; 252271-82-2P; 308845-80-9P; 1178896-02-0P; 1178896-07-5P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. of dichloropyrazinones via Strecker reaction of primary amines, aldehydes, and trimethylsilyl cyanide, followed by cyclocondensation with oxalyl chloride under microwave irradn.); 87486-37-1P; 173200-35-6P; 173200-36-7P; 199296-26-9P; 308845-81-0P; 595581-85-4P; 602280-43-3P; 1178895-95-8P; 1178895-96-9P; 1178895-97-0P; 1178895-98-1P; 1178895-99-2P; 1178896-00-8P; 1178896-01-9P; 1178896-03-1P; 1178896-04-2P; 1178896-05-3P; 1178896-06-4P Role: SPN (Synthetic preparation), PREP (Preparation) (prepn. of dichloropyrazinones via Strecker reaction of primary amines, aldehydes, and trimethylsilyl cyanide, followed by cyclocondensation with oxalyl chloride under microwave irradn.)

    Available from: 2009-11-24 Created: 2009-11-24 Last updated: 2018-01-12Bibliographically approved
    4. Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
    Open this publication in new window or tab >>Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
    Show others...
    2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 17, p. 6512-6525Article in journal (Refereed) Published
    Abstract [en]

    Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.

    Keywords
    Hepatitis C virus NS3 protease, Protease inhibitors, 2(1H)-pyrazinone, Phenylglycine
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-111366 (URN)10.1016/j.bmc.2010.06.101 (DOI)000281203300032 ()20673728 (PubMedID)
    Note

    Uppdaterad från manuskript till Artikel 20101206

    Available from: 2009-12-16 Created: 2009-12-11 Last updated: 2018-01-12Bibliographically approved
  • 357.
    Örtqvist, Pernilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    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 Biochemistry and Organic Chemistry, Biochemistry.
    Vema, Aparna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Borg, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones2010In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 17, p. 6512-6525Article in journal (Refereed)
    Abstract [en]

    Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.

  • 358.
    Örtqvist, Pernilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vema, Aparna
    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 Biochemistry and Organic Chemistry.
    Dahl, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Rönn, Robert
    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.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Structure-Activity Relationships of HCV NS3 Protease Inhibitors Evaluated on the Drug-Resistant Variants A156T and D168VManuscript (preprint) (Other academic)
5678 351 - 358 of 358
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