Download MendeleyAn orally bioavailable HIV-1 protease inhibitor containing an imidazole-derived peptide bond replacement: crystallographic and pharmacokinetic analysis.
Abdel-Meguid, S.S., Metcalf, B.W., Carr, T.J., Demarsh, P., DesJarlais, R.L., Fisher, S., Green, D.W., Ivanoff, L., Lambert, D.M., Murthy, K.H.M., Petteway Jr., S.R., Pitts, W.J., Tomaszek Jr., T.A., Winborne, E., Zhao, B., Dreyer, G.B., Meek, T.D.(1994) Biochemistry 33: 11671-11677
- PubMed: 7918383
- DOI: https://doi.org/10.1021/bi00205a001
- Primary Citation of Related Structures:
1SBG - PubMed 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.
Organizational Affiliation:
Department of Macromolecular Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
