title: An orally bioavailable HIV-1 protease inhibitor containing an imidazole-derived peptide bond replacement: crystallographic and pharmacokinetic analysis.
abstract: (2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) amino-6-phenylhexanoyl-N-(1'-imidazo-2-yl)-2'-methylpropanamide (compound 2) is a tripeptide analogue inhibitor of HIV-1 protease in which a C-terminal imidazole substituent constitutes an isoelectronic, structural mimic of a carboxamide group. Compound 2 is a potent inhibitor of the protease (K(i) = 18 nM) and inhibits HIV-1 acute infectivity of CD4+ T-lymphocytes (IC50 = 570 nM). Crystallographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydrogen-bonding interactions with the protease as amide linkages in other peptide analogue inhibitors. The sole substitution of the C-terminal carboxamide of a hydroxyethylene-containing tripeptide analogue with an imidazole group imparts greatly improved pharmacokinetic and oral bioavailability properties on the compound compared to its carboxamide-containing homologue (compound 1). While the oral bioavailability of compound 1 in rats was negligible, compound 2 displayed oral bioavailabilities of 30% and 14%, respectively, in rats and monkeys.
authors.affiliation: Department of Macromolecular Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
authors.forename: S S
authors.initials: SS
authors.lastname: Abdel-Meguid
authors.forename: B W
authors.initials: BW
authors.lastname: Metcalf
authors.forename: T J
authors.initials: TJ
authors.lastname: Carr
authors.forename: P
authors.initials: P
authors.lastname: Demarsh
authors.forename: R L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: S
authors.initials: S
authors.lastname: Fisher
authors.forename: D W
authors.initials: DW
authors.lastname: Green
authors.forename: L
authors.initials: L
authors.lastname: Ivanoff
authors.forename: D M
authors.initials: DM
authors.lastname: Lambert
authors.forename: K H
authors.initials: KH
authors.lastname: Murthy
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D005069:Evaluation Studies as Topic; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects*; D015497:HIV-1 / Q000201:enzymology*; D006207:Half-Life; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D008968:Molecular Conformation; D018716:Molecular Mimicry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C089787:2-phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl)amino-6-phenylhexanoyl-N-(1'-imidazol-2-yl)-2-'-methylpropanamide; D007093:Imidazoles; D016333:HIV Protease