AN ORALLY BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE-BOND REPLACEMENT - CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS

y-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 constitute s 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). Crystall ographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydroge n-bonding interactions with the protease as amide linkages in other pe ptide analogue inhibitors. The sole substitution of the C-terminal car boxamide of a hydroxyethylene-containing tripeptide analogue with an i midazole group imparts greatly improved pharmacokinetic and oral bioav ailability properties on the compound compared to its carboxamide-cont aining homologue (compound I). While the oral bioavailability of compo und 1 in rats was negligible, compound 2 displayed oral bioavailabilit ies of 30% and 14%, respectively, in rats and monkeys.