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


  • (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.

published proceedings

  • Biochemistry

altmetric score

  • 3

author list (cited authors)

  • Abdel-Meguid, S. S., Metcalf, B. W., Carr, T. J., Demarsh, P., DesJarlais, R. L., Fisher, S., ... Murthy, K. H.

citation count

  • 65

complete list of authors

  • Abdel-Meguid, SS||Metcalf, BW||Carr, TJ||Demarsh, P||DesJarlais, RL||Fisher, S||Green, DW||Ivanoff, L||Lambert, DM||Murthy, KH

publication date

  • October 1994