Inhibitors of hepatitis C virus NS3.4A protease. Part 3: P2 proline variants.
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.
Perni
Robert B
RB
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. robert_perni@vrtx.com
Farmer
Luc J
LJ
Cottrell
Kevin M
KM
Court
John J
JJ
Courtney
Lawrence F
LF
Deininger
David D
DD
Gates
Cynthia A
CA
Harbeson
Scott L
SL
Kim
Joseph L
JL
Lin
Chao
C
Lin
Kai
K
Luong
Yu-Ping
YP
Maxwell
John P
JP
Murcko
Mark A
MA
Pitlik
Janos
J
Rao
B Govinda
BG
Schairer
Wayne C
WC
Tung
Roger D
RD
Van Drie
John H
JH
Wilson
Keith
K
Thomson
John A
JA
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
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