title: Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors.
abstract: The design, synthesis, and biological evaluation of novel C3-substituted cyclopentyltetrahydrofuranyl (Cp-THF)-derived HIV-1 protease inhibitors are described. Various C3-functional groups on the Cp-THF ligand were investigated in order to maximize the ligand-binding site interactions in the flap region of the protease. Inhibitors 3c and 3d have displayed the most potent enzyme inhibitory and antiviral activity. Both inhibitors have maintained impressive activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 3c-bound HIV-1 protease revealed a number of important molecular insights into the ligand-binding site interactions.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Chapsal
authors.forename: Melinda
authors.initials: M
authors.lastname: Steffey
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000069454:Darunavir; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D014520:Urethane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D003517:Cyclopentanes; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D014520:Urethane; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir