- Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings
-
Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent Ki* of 5.3 nM and activity in replicon (EC90) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 μM h.
- Chen, Kevin X.,Vibulbhan, Bancha,Yang, Weiying,Nair, Latha G.,Tong, Xiao,Cheng, Kuo-Chi,Njoroge, F. George
-
body text
p. 1105 - 1109
(2009/08/07)
-
- Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies
-
Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-α or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only ~50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P3 sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P3 sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.
- Venkatraman, Srikanth,Blackman, Mellissa,Wu, Wanli,Nair, Latha,Arasappan, Ashok,Padilla, Angela,Bogen, Stéphane,Bennett, Frank,Chen, Kevin,Pichardo, John,Tong, Xiao,Prongay, Andrew,Cheng, Kuo-Chi,Girijavallabhan, Viyyoor,George Njoroge
-
experimental part
p. 4486 - 4495
(2009/10/10)
-