An Orally Bioavailable HIV-1 Protease Inhibitor Containing an Imidazole-Derived Peptide Bond Replacement: Crystallographic and Pharmacokinetic Analysis

(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...

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Bibliographic Details
Published in:Biochemistry (Easton) 1994-10, Vol.33 (39), p.11671-11677
Main Authors: Abdel-Meguid, Sherin S, Metcalf, Brian W, Carr, Thomas J, Demarsh, Peter, DesJarlais, Renee L, Fisher, Seth, Green, David W, Ivanoff, Lucinda, Lambert, Dennis M
Format: Article
Language:English
Subjects:
Administration, Oral
AIDS/HIV
Animals
Biological Availability
Crystallography, X-Ray
Evaluation Studies as Topic
Half-Life
HIV Protease - chemistry
HIV Protease - drug effects
HIV-1 - enzymology
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacokinetics
Macaca fascicularis
Metabolic Clearance Rate
Molecular Conformation
Molecular Mimicry
Rats
Rats, Sprague-Dawley
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Summary:(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.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi00205a001