Toward the back-up of boceprevir (SCH 503034): discovery of new extended P4-capped ketoamide inhibitors of hepatitis C virus NS3 serine protease with improved potency and pharmacokinetic profiles.
Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket and optimization of the P(1)' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P(4)-capped inhibitors were also found to have improved PK profile.
Bogen
Stéphane L
SL
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. stephane.bogen@spcorp.com
Pan
Weidong
W
Ruan
Sumei
S
Nair
Latha G
LG
Arasappan
Ashok
A
Bennett
Frank
F
Chen
Kevin X
KX
Jao
Edwin
E
Venkatraman
Srikanth
S
Vibulbhan
Bancha
B
Liu
Rong
R
Cheng
Kuo-Chi
KC
Guo
Zhuyan
Z
Tong
Xiao
X
Saksena
Anil K
AK
Girijavallabhan
Viyyoor
V
Njoroge
F George
FG
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D055808:Drug Discovery; D016679:Genome, Viral / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000187:drug effects; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D011392:Proline; D012367:RNA, Viral; 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; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide