title: Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2' side chains.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA. smithhab@sas.upenn.edu
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Adam K
authors.initials: AK
authors.lastname: Charnley
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Beiger
authors.forename: Louis-David
authors.initials: LD
authors.lastname: Cantin
authors.forename: Craig S
authors.initials: CS
authors.lastname: Kenesky
authors.forename: Ralph
authors.initials: R
authors.lastname: Hirschmann
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Mark W
authors.initials: MW
authors.lastname: Stahlhut
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D011760:Pyrrolidinones; D016333:HIV Protease