title: Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease.
abstract: Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nigel_liverton@merck.com
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: Jillian
authors.initials: J
authors.lastname: DiMuzio
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gilbert
authors.forename: Shi-Shan
authors.initials: SS
authors.lastname: Mao
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Romano
authors.forename: Mark
authors.initials: M
authors.lastname: Stahlhut
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000818:Animals; D016174:Hepacivirus / Q000201:enzymology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D047028:Macrocyclic Compounds; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases