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Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease

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Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 53 Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease Focus on C-Terminal Acyl Sulfonamides ROBERT RÖNN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 UPPSALA ISBN 978-91-554-6862-0 2007 urn:nbn:se:uu:diva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“Det finns inga genvägar till framgång” Gunde Svan Papers Included in this Thesis This thesis is based on the following papers, which are referred to in the text by their Roman numerals: I Rönn, R.; Sabnis, Y. A.; Gossas, T.; Åkerblom, E.; Danielson, U. H.; Hallberg, A.; Johansson, A. Exploration of Acyl Sulfona- mides as Carboxylic Acid Replacements in Protease Inhibitors of the Hepatitis C Virus Full-Length NS3. Bioorg. Med. Chem. 2006, 14, 544–559. II Rönn, R.; Gossas, T.; Sabnis, Y. A.; Daoud, H.; Åkerblom, E.; Danielson, U. H.; Sandström, A. Evaluation of a Diverse Set of Potential P1 Carboxylic Acid Bioisosteres in Hepatitis C Virus NS3 Protease Inhibitors. Bioorg. Med. Chem. Accepted. III Wu, X.; Rönn, R.; Gossas, T.; Larhed, M. Easy-to-Execute Car- bonylations: Microwave Synthesis of Acyl Sulfonamides Using Mo(CO)6 as a Solid Carbon Monoxide Source. J. Org. Chem. 2005, 70, 3094–3098. IV Rönn, R.; Lampa, A.; Peterson, S. D.; Gossas, T.; Åkerblom, E.; Danielson, U. H.; Karlén, A.; Sandström, A. Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moi- ety. Submitted. Reprints are presented with permission from the publishers. Contents 1 Introduction..............................................................................................11 1.1 Hepatitis C Virus................................................................................11 1.1.1 Prevalence and Transmission of HCV........................................11 1.1.2 Outcome and Symptoms of an HCV Infection...........................12 1.1.3 The Virus and its Life Cycle.......................................................13 1.1.4 The Viral Genome and its Translational Products......................15 1.1.5 HCV Variability..........................................................................17 1.1.6 Current Treatment of Hepatitis C ...............................................17 1.1.7 HCV Drug Discovery .................................................................18 1.2 The HCV NS3 Protease......................................................................19 1.2.1 Proteases in General and Serine Proteases in Particular.............19 1.2.2 Structure and Function of the HCV NS3 Protease......................21 1.2.3 HCV NS3 Protease Inhibitors.....................................................22 2 Aims of the Present Study .......................................................................31 3 Carboxylic Acid Bioisosteres in HCV NS3 Protease Inhibitors (Papers I and II)..........................................................................................32 3.1 Bioisosteres in Medicinal Chemistry .................................................32 3.2 Exploring the Acyl Sulfonamide Group (Paper I)..............................32 3.2.1 Preparation of Tetrapeptides.......................................................34 3.2.2 Preparation of Tripeptides ..........................................................35 3.2.3 Structure–Activity Relationship .................................................37 3.3 Potential P1 Carboxylic Acid Bioisosteres (Paper II).........................42 3.3.1 Chemistry....................................................................................42 3.3.2 Structure–Activity Relationship .................................................44 3.3.3 pH Study.....................................................................................46 4 Synthesis of Aryl Acyl Sulfonamides (Paper III) ..................................49 4.1 Palladium-Catalyzed Carbonylation...................................................49 4.2 Carbon Monoxide Sources .................................................................50 4.3 Microwaves as a Tool in Drug Discovery..........................................50 4.4 Method Development.........................................................................51 4.5 A Medicinal Chemistry Application ..................................................54 5 A Novel Aromatic P1 Moiety in HCV NS3 Protease Inhibitors (Paper IV) ....................................................................................................56 5.1 Chemistry ...........................................................................................57 5.2 Structure–Activity Relationship.........................................................58 6 Concluding Remarks ...............................................................................62 7 Acknowledgements ..................................................................................64 8 References.................................................................................................66 Abbreviations and Definitions ACCA 1-amino-cyclopropanecarboxylic acid ACE angiotensin-converting enzyme ADME absorption, distribution, metabolism and excretion Ala alanine Arg arginine Asp aspartic acid ATP adenosine triphosphate Bn benzyl Boc tert-butoxycarbonyl CDI 1,1´-carbonyldiimidazole Cha cyclohexylalanine Chg cyclohexylglycine CMV cytomegalovirus CNS central nervous system DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIC N,N´-diisopropylcarbodiimide DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPIV dipeptidyl peptidase IV EC50 inhibitor concentration giving 50% inhibition of replica- tion in a cell-based system ER endoplasmic reticulum Fmoc 9-fluorenylmethoxycarbonyl Gln glutamine Glu glutamic acid Gly glycine HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- yl-methylene]-N-methylmethanaminium hexafluo- rophosphate N-oxide HBTU N-[(1H-benzotriazole-1-yl)-(dimethylamino)methylene]- N-methylmethanaminium hexafluorophosphate N-oxide HCV hepatitis C virus His histidine HIV human immunodeficiency virus HLE human leukocyte elastase HSV herpes simplex virus HTS high-throughput screening IC50 inhibitor concentration giving 50% inhibition IFN interferon Ile isoleucine IRBM Istituto di Ricerche di Biologia Molecolare IRES internal ribosome entry site Ki inhibition constant or dissociation constant for inhibitor binding Ki* overall inhibition constant for covalent inhibitors Leu leucine Lys lysine 2-Nal 2-naphthylalanine NMM N-methylmorpholine NTP nucleotide triphosphate NTR non-translated region Nva norvaline PEG polyethylene glycol Ph phenyl ptol para-tolyl RdRp RNA-dependent RNA polymerase SAR structure–activity relationship Ser serine SPPS solid phase peptide synthesis Suc succinic acid SVR sustained virological response TBTU N-[(1H-benzotriazole-1-yl)-(dimethylamino)methylene]- N-methylmethanaminium tetrafluoroborate N-oxide TES triethylsilane TFA trifluoroacetic acid THF tetrahydrofuran Thr threonine TMP 2,4,6-trimethylpyridine Val valine vinyl-ACCA (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid 1 Introduction 1.1 Hepatitis C Virus In the mid 1970s, it was proposed that a viral agent apart from hepatitis type A or B caused transfusion-associated hepatitis (inflammation of the liver).1 In 1989, several years after its recognition, this viral agent causing non-A, non-B hepatitis was identified and termed hepatitis C virus (HCV).2 1.1.1 Prevalence and Transmission of HCV Today, approximately three decades after the recognition of HCV, the virus is considered to be a new global epidemic. Estimates of the global preva- lence of HCV reveal that the virus affects ~120–180 million people, repre- senting ~2–3% of the world’s population.3,4 HCV is recognized as a major cause of chronic liver disease as well as the leading cause of liver transplan- tations in developed countries.5 Furthermore, mathematical models predict that HCV-related mortality will rise during the coming decades.6-9 There are large geographical differences in the prevalence of HCV; the countries with the highest prevalence rates being found in Africa and Asia (Figure 1). Egypt is by far the most affected country in the world, with re- ported prevalence rates up to 22%.10 Figure 1. Estimated global prevalence of HCV.3 11 HCV is a bloodborne infection with three major routes of transmission. In- jection drug use is the primary route of transmission in the developed coun- tries while unsafe therapeutic injections
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