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  • The introduction of P4 subs...
    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

    Bioorganic & medicinal chemistry letters, 04/2010, Volume: 20, Issue: 8
    Journal Article

    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.

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