title: P4 and P1' optimization of bicycloproline P2 bearing tetrapeptidyl alpha-ketoamides as HCV protease inhibitors.
abstract: With the aim of improving HCV protease inhibitors reported in our previous manuscripts, we synthesized and evaluated a series of 1a-based tetrapeptidyl alpha-ketoamides with additional P4 modification. The promising analog discovered through this SAR, 5a, was further derivatized at P1' or P1 position. As a result of these efforts, we found that replacement of the P4 valine as seen in 1a with cyclohexylglycine (Chg) resulted in the discovery of 5a, 5c, and 5e endowed with improved cellular activity in comparison to 1a.
authors.affiliation: Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Yip
authors.forename: Frantz
authors.initials: F
authors.lastname: Victor
authors.forename: Jason
authors.initials: J
authors.lastname: Lamar
authors.forename: Robert
authors.initials: R
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: Nathan
authors.initials: N
authors.lastname: Yumibe
authors.forename: Mark
authors.initials: M
authors.lastname: Wakulchik
authors.forename: John
authors.initials: J
authors.lastname: Munroe
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D012093:Replicon / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000577:Amides; D000998:Antiviral Agents; 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