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-I 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 I). 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.