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

• Published in: Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (8), p.2617-2621
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Area Under Curve; Biological and medical sciences; Biological Availability; Crystallography, X-Ray; Haplorhini; Hepatitis C virus; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - chemistry; Proline - pharmacokinetics; Proline - pharmacology; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Rats; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.063

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.