title: Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation.
abstract: The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (-)-7, was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure-activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States. 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: Abigail
authors.initials: A
authors.lastname: Baldridge
authors.forename: Melinda P
authors.initials: MP
authors.lastname: Steffey
authors.forename: D Eric
authors.initials: DE
authors.lastname: Walters
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D024921:Drug Resistance, Multiple, Viral; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002219:Carbamates; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; C556315:hexahydro-2H-furo(2,3-b)pyran-4-yl-(2S,3R)-4-(N-isobutyl-4-methoxyphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl carbamate; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1