title: Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue.
abstract: Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (Ki* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. kevin.chen@spcorp.com
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Weiying
authors.initials: W
authors.lastname: Yang
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Nancy
authors.initials: N
authors.lastname: Butkiewicz
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000818:Animals; D001682:Biological Availability; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D011392:Proline; D015842:Serine Proteinase Inhibitors; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C006865:butylurea