Potent HIV Protease Inhibitors Containing a Novel (Hydroxyethyl)amide Isostere

Abstract

A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.

On the role of theRconfiguration of the reaction-intermediate isostere in HIV-1 protease-inhibitor binding: X-ray structure at 2.0 Å resolution

“…The character of the hydroxyethylamide isostere of the HIV-2 protease inhibitor, QNC-THR-PHM-RHS (Beaulieu et al, 1997), resembles that of our isosteric group. However, compared with RE, the hydrogen bonds and hydrophobic interactions have a completely different scheme and the molecules are shifted against each other (based on the superposition of protein C atoms) by 1.68 Å .…”

“…This fact is exploited in substrate-based inhibitor design, in which the scissile bond is replaced by a non-cleavable isostere. Various types of inhibitors have been proposed, with the isostere based on hydroxyethylene (Jaskolski et al, 1991), hydroxyethylamine (Kervinen et al, 1996) or reduced amide (Beaulieu et al, 1997). Other types of inhibitors were based on derivatives of urea (Jadhav et al, 1997), penicillin (Jhoti et al, 1994), phosphinate (Abdel-Meguid et al, 1993), sulfonamide (Backbro et al, 1997) and difluoroketone (Silva et al, 1996).…”

2‘,6‘-Dimethylphenoxyacetyl: A New Achiral High Affinity P3-P2Ligand for Peptidomimetic-Based HIV Protease Inhibitors

“…The more than 300-fold difference between the observed K i and the EC 50 values for compound 27 is probably the result of a number of factors including protein binding, metabolism, and its ability to enter cells. Furthermore, experimental conditions used in enzymology studies may not reflect conditions found in the cell (similar observations were made previously in the case of palinavir 4a and hydroxyethylamide inhibitors 19 ). The apparent bioavailability of 27 in the rat was 61%, and at 5 mg/kg oral doses, it achieved plasma concentrations in excess of 900 nM with a clearance half-life of 0.4 h. 16a The apparent oral bioavailability of 27 when administered in the dog was 39% and that in chimpanzee was 5%, for an oral dose of 10 mg/kg and iv doses of 1 mg/kg and 0.5 mg/ kg, respectively.…”

Synthesis and cathepsin D inhibition of peptide-hydroxyethyl amine isosteres with cyclic tertiary amines

“…[21,22] The use of hydroxyethyl isosteres with cyclic tertiary amines have lead to compounds with enhanced oral absorption.J23] In recent years the (R)-hydroxyethylamine insert was incorporated as a key component of many clinically used, highly potent, HIV-1 protease inhibitors. Initially several compounds with hydroxyethyl amine isosteres with flexible alkyl amine were developed [24], but suffered limited in vivo half-lives and were not therapeutically useful.…”