951789-91-6Relevant academic research and scientific papers
Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups
Venkatraman, Srikanth,Velazquez, Francisco,Wu, Wanli,Blackman, Melissa,Madison, Vincent,Njoroge, F. George
scheme or table, p. 2151 - 2155 (2010/06/19)
Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P1 had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P1 group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir.
Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings
Chen, Kevin X.,Vibulbhan, Bancha,Yang, Weiying,Nair, Latha G.,Tong, Xiao,Cheng, Kuo-Chi,Njoroge, F. George
scheme or table, p. 1105 - 1109 (2009/08/07)
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.
Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease
Chen, Kevin X.,Nair, Latha,Vibulbhan, Bancha,Yang, Weiying,Arasappan, Ashok,Bogen, Stephane L.,Venkatraman, Srikanth,Bennett, Frank,Pan, Weidong,Blackman, Melissa L.,Padilla, Angela I.,Prongay, Andrew,Cheng, Kuo-Chi,Tong, Xiao,Shih, Neng-Yang,Njoroge, F. George
scheme or table, p. 1370 - 1379 (2009/12/26)
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 tr
Practical and efficient method for amino acid derivatives containing β-quaternary center: application toward synthesis of hepatitis C virus NS3 serine protease inhibitors
Arasappan, Ashok,Venkatraman, Srikanth,Padilla, Angela I.,Wu, Wanli,Meng, Tao,Jin, Yan,Wong, Jesse,Prongay, Andrew,Girijavallabhan, Viyyoor,George Njoroge
, p. 6343 - 6347 (2008/02/10)
A practical and efficient route toward synthesis of amino acid derivatives containing β-quaternary center has been developed using diastereoselective Strecker reaction. The method was employed for preparation of >100 g of β-methylcyclohexyl glycine deriva
