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

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.

Molecular Recognition of Protein−Ligand Complexes: Applications to Drug Design

“…To reduce the peptidic nature of hydroxyethylene inhibitors the SmithKline group has reported on using an imidazole ring as an amide bond replacement. Crystal structures for two of these compounds, SB203386 , K i = 18.0 nM (PDB entry: 1SBG), and SB206343 , K i = 0.6 nM (PDB entry: 1HPS), have been reported. (See Figure AP*7.)…”

“…The related triazole analog AP-16 , is a more potent inhibitor ( K i = 4.2 nM). Since the p K a of a triazole, in general, is lower than that of an imidazole, the more potent inhibition by AP-16 , which is presumably unprotonated at 6.0, suggests that the neutral forms of these compounds are the species that potently inhibits the enzyme …”

L-Proline Triflate as an Efficient and Reusable Catalyst for the One-Pot Synthesis of 2,4,5-Trisubstituted Imidazoles and 1,2,4,5-Tetrasubstituted Imidazoles

“…Imidazole derivatives are of considerable interest in the pharmaceutical industry as well as in academia due to their promising biological activities such as inhibitors of p38 MAP kinase, 1 B-Raf kinase, 2 orally bioavailable HIV-1 protease inhibitors, 3 antitumour, 4 therapeutic agents, 5 plant growth regulators, 6 glucagon receptors 7 and antibacterial agents. 8 Thus, the synthesis of this heterocyclic nucleus is of great interest.…”

Heterocyclic HIV-1 Protease Inhibitors

“…There was one final consideration in choosing the imidazole and the other aromatic heterocycles as a component of our design: namely, that these heterocycles have already been utilized in HIV-1 protease inhibitors to improve the water solubility and oral bioavailability of the final compound . The major difference between the prior use of the heterocycles and the use outlined in this paper is that the heterocycles are proposed to interact directly within the active site in this work rather than their previous peripheral inclusion.…”

“…For example, the active site chemical functionality in HIV-1 protease has been reported to form a copper(II) chelatedesigned by comparison with small molecule organometallics . In addition, researchers at Pharmacia & Upjohn, Inc. are developing a class of HIV-1 protease inhibitors which do contain a hydroxyl group to hydrogen bond to the active site, but which is not part of a stereogenic center 6d…”