title: Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease: secondary amide series.
abstract: The design, synthesis, and crystallographic analysis of protein-inhibitor complexes is described for a novel series of nonpeptidic HIV protease (HIV Pr)inhibitors. Beginning with a cocrystal structure of a Phe-Pro peptidomimetic bound to the HIV Pr, design was initiated that resulted in the substituted 2-butanol compound 8 as the lead compound (Ki = 24.5 microM, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, Ki = 0.48 microM). These inhibitors were found to bind to the enzyme essentially as predicted on the basis of the original design hypothesis. Stereospecific synthesis of individual enantiomers confirmed the prediction of a binding preference for the S alcohol stereochemistry. Modest antiviral activity was demonstrated for several of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.
authors.affiliation: Agouron Pharmaceuticals, Inc, San Diego, California 92121, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Reich
authors.forename: M
authors.initials: M
authors.lastname: Melnick
authors.forename: M J
authors.initials: MJ
authors.lastname: Pino
authors.forename: M A
authors.initials: MA
authors.lastname: Fuhry
authors.forename: A J
authors.initials: AJ
authors.lastname: Trippe
authors.forename: K
authors.initials: K
authors.lastname: Appelt
authors.forename: J F
authors.initials: JF
authors.lastname: Davies
authors.forename: B W
authors.initials: BW
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Musick
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D000440:Butanols / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000998:Antiviral Agents; D000440:Butanols; D017320:HIV Protease Inhibitors; C043958:2-butanol