title: Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease.
abstract: The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA 94404, USA. csheng@gilead.com
authors.forename: X Christopher
authors.initials: XC
authors.lastname: Sheng
authors.forename: Todd
authors.initials: T
authors.lastname: Appleby
authors.forename: Thomas
authors.initials: T
authors.lastname: Butler
authors.forename: Ruby
authors.initials: R
authors.lastname: Cai
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Chen
authors.forename: Aesop
authors.initials: A
authors.lastname: Cho
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.forename: Jeromy
authors.initials: J
authors.lastname: Cottell
authors.forename: William E
authors.initials: WE
authors.lastname: Delaney
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.forename: John
authors.initials: J
authors.lastname: Link
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Ji
authors.forename: Rowchanak
authors.initials: R
authors.lastname: Pakdaman
authors.forename: Hyung-Jung
authors.initials: HJ
authors.lastname: Pyun
authors.forename: Qiaoyin
authors.initials: Q
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008252:Macaca fascicularis; D008958:Models, Molecular; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; 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: D000998:Antiviral Agents; D002264:Carboxylic Acids; D011804:Quinolines; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C573362:GS-9451; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases