Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease.
The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC(90) by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K(i)* = 4 nM, EC(90) = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K(i)* = 4 nM, EC(90) = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
Chen
Kevin X
KX
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. kevin.chen@spcorp.com
Nair
Latha
L
Vibulbhan
Bancha
B
Yang
Weiying
W
Arasappan
Ashok
A
Bogen
Stephane L
SL
Venkatraman
Srikanth
S
Bennett
Frank
F
Pan
Weidong
W
Blackman
Melissa L
ML
Padilla
Angela I
AI
Prongay
Andrew
A
Cheng
Kuo-Chi
KC
Tong
Xiao
X
Shih
Neng-Yang
NY
Njoroge
F George
FG
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006860:Hydrogen Bonding; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D010881:Piperidones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D007094:Imides; D007930:Leucine; D010881:Piperidones; D015842:Serine Proteinase Inhibitors; D014508:Urea; D017361:Viral Nonstructural Proteins; C550362:N-(1-(cyclopropylmethyl)-2,3-dioxo-3-(2-propenylamino)propyl)-3-(2-((((1-((4,4-dimethyl-2,6-dioxo-1-piperidinyl)methyl)-2,2-dimethylpropyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexane-2-carboxamide; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C417575:leucinol