title: Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
abstract: Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.
authors.affiliation: Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bäck
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Johansson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wångsell
authors.forename: Fredrik
authors.initials: F
authors.lastname: Thorstensson
authors.forename: Ingemar
authors.initials: I
authors.lastname: Kvarnström
authors.forename: Susana
authors.initials: S
authors.lastname: Ayesa
authors.forename: Horst
authors.initials: H
authors.lastname: Wähling
authors.forename: Mikael
authors.initials: M
authors.lastname: Pelcman
authors.forename: Katarina
authors.initials: K
authors.lastname: Jansson
authors.forename: Stefan
authors.initials: S
authors.lastname: Lindström
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Björn
authors.initials: B
authors.lastname: Classon
authors.forename: Christina
authors.initials: C
authors.lastname: Rydergård
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Sa
authors.initials: S
authors.lastname: Rosenquist
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D003500:Cyclization; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D003517:Cyclopentanes; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D047028:Macrocyclic Compounds; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases