Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2′ side chains

• Published in: Bioorganic & medicinal chemistry letters 2006-02, Vol.16 (4), p.859-863
• Main Authors: Smith, Amos B., Charnley, Adam K., Harada, Hironori, Beiger, Jason J., Cantin, Louis-David, Kenesky, Craig S., Hirschmann, Ralph, Munshi, Sanjeev, Olsen, David B., Stahlhut, Mark W., Schleif, William A., Kuo, Lawrence C.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cattle; Crystallography, X-Ray; Drug Design; HIV Protease - drug effects; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1; Human immunodeficiency virus 1; Humans; In Vitro Techniques; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Mutation; Pharmacology. Drug treatments; Protease inhibitors; Pyrrolidinones - chemical synthesis; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Pyrrolinone; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.11.011

A series of monopyrrolinone-based HIV-1 protease inhibitors were synthesized and evaluated for activity against wild-type and mutant forms of the virus. X-ray cocrystal structures provide insight into their potent activity. A series of monopyrrolinone-based HIV-1 protease inhibitors possessing rationally designed P2′ side chains have been synthesized and evaluated for activity against wild-type HIV-1 protease. The most potent inhibitor displays subnanomolar potency in vitro for the wild-type HIV-1 protease. Additionally, the monopyrrolinone inhibitors retain potency in cellular assays against clinically significant mutant forms of the virus. X-ray structures of these inhibitors bound in the wild-type enzyme reveal important insights into the observed biological activity.