855428-40-9Relevant academic research and scientific papers
The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: A change in direction in the search for a second generation HCV NS3 protease inhibitor
Bennett, Frank,Huang, Yuhua,Hendrata, Siska,Lovey, Raymond,Bogen, Stephane L.,Pan, Weidong,Guo, Zhuyan,Prongay, Andrew,Chen, Kevin X.,Arasappan, Ashok,Venkatraman, Srikanth,Velazquez, Francisco,Nair, Latha,Sannigrahi, Mousumi,Tong, Xiao,Pichardo, John,Cheng, Kuo-Chi,Girijavallabhan, Viyyoor M.,Saksena, Anil K.,Njoroge, F. George
scheme or table, p. 2617 - 2621 (2010/07/05)
In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir 1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
