title: P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.
abstract: With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50mg/kg, 3a achieved 2.5x higher liver and plasma exposure in comparison to that detected with 1a.
authors.affiliation: Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Frantz
authors.initials: F
authors.lastname: Victor
authors.forename: Jason
authors.initials: J
authors.lastname: Lamar
authors.forename: Nancy
authors.initials: N
authors.lastname: Snyder
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Yip
authors.forename: Deqi
authors.initials: D
authors.lastname: Guo
authors.forename: Nathan
authors.initials: N
authors.lastname: Yumibe
authors.forename: Robert B
authors.initials: RB
authors.lastname: Johnson
authors.forename: Q May
authors.initials: QM
authors.lastname: Wang
authors.forename: John I
authors.initials: JI
authors.lastname: Glass
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D008297:Male; D011392:Proline / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D001643:Bridged Bicyclo Compounds; D011392:Proline; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases