title: Inhibitors of hepatitis C virus NS3.4A protease. Part 3: P2 proline variants.
abstract: We recently described the identification of an optimized alpha-ketoamide warhead for our series of HCV NS3.4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P(2). These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S(2) binding pocket as the defining pharmacophore for inhibition of the NS3.4A enzyme.
authors.affiliation: Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. robert_perni@vrtx.com
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Farmer
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Cottrell
authors.forename: John J
authors.initials: JJ
authors.lastname: Court
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Courtney
authors.forename: David D
authors.initials: DD
authors.lastname: Deininger
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Gates
authors.forename: Scott L
authors.initials: SL
authors.lastname: Harbeson
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.forename: Kai
authors.initials: K
authors.lastname: Lin
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Luong
authors.forename: John P
authors.initials: JP
authors.lastname: Maxwell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Murcko
authors.forename: Janos
authors.initials: J
authors.lastname: Pitlik
authors.forename: B Govinda
authors.initials: BG
authors.lastname: Rao
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Schairer
authors.forename: Roger D
authors.initials: RD
authors.lastname: Tung
authors.forename: John H
authors.initials: JH
authors.lastname: Van Drie
authors.forename: Keith
authors.initials: K
authors.lastname: Wilson
authors.forename: John A
authors.initials: JA
authors.lastname: Thomson
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D006526:Hepatitis C / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D011392:Proline; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus