Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease.
Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
Liverton
Nigel J
NJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nigel_liverton@merck.com
Holloway
M Katharine
MK
McCauley
John A
JA
Rudd
Michael T
MT
Butcher
John W
JW
Carroll
Steven S
SS
DiMuzio
Jillian
J
Fandozzi
Christine
C
Gilbert
Kevin F
KF
Mao
Shi-Shan
SS
McIntyre
Charles J
CJ
Nguyen
Kevin T
KT
Romano
Joseph J
JJ
Stahlhut
Mark
M
Wan
Bang-Lin
BL
Olsen
David B
DB
Vacca
Joseph P
JP
D000818:Animals; D016174:Hepacivirus / Q000201:enzymology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D047028:Macrocyclic Compounds; 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