An orally bioavailable HIV-1 protease inhibitor containing an imidazole-derived peptide bond replacement: crystallographic and pharmacokinetic analysis.

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

An orally bioavailable HIV-1 protease inhibitor containing an imidazole-derived peptide bond replacement: crystallographic and pharmacokinetic analysis.

Biochemistry. 1994 Oct 4;33(39):11671-7. Unique Identifier : AIDSLINE MED/95001874
Abdel-Meguid SS; Metcalf BW; Carr TJ; Demarsh P; DesJarlais RL; Fisher S; Green DW; Ivanoff L; Lambert DM; Murthy KH; et al; Department of Macromolecular Sciences, SmithKline Beecham; Pharmaceuticals, King of Prussia, Pennsylvania 19406.

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.

Keywords: Administration, Oral Animal Biological Availability Crystallography, X-Ray Evaluation Studies Half-Life HIV Protease/CHEMISTRY/*DRUG EFFECTS HIV-1/*ENZYMOLOGY Imidazoles/*CHEMISTRY/CHEMICAL SYNTHESIS/PHARMACOKINETICS Macaca fascicularis Metabolic Clearance Rate Molecular Conformation Molecular Mimicry Rats Rats, Sprague-Dawley JOURNAL ARTICLE
950130
M9510810

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