Donna Ferguson

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

A topliss tree analysis of the HIV-protease inhibitory activity of 6-phenyl-4-hydroxy-pyran-2-ones

Abstract In a study of 4-hydroxy-pyran-2-ones as possible inhibitors of HIV protease, a series of compounds were synthesized following the Topliss operational scheme for substitution on a phenyl group at the 6 position of the pyrone. In addition, a number of compounds with polar substituents were made.

Nonpeptidic HIV protease inhibitors: 3-(S-benzyl substituted)-4-hydroxy-6-(phenyl substituted)-2H-pyran-2-one with an inverse mode of binding

Abstract Systematic substitutions on 6-phenyl and 3-SCH 2 Ph rings of inhibitor 1 , were carried out to optimize the inhibitory activity against HIV PR. These studies lead to 3-Sbenzyl esters with enhanced potency. The X-ray crystal structure of 32 bound to HIV PR revealed that the 3-SCH 2 phenyl group is occupying the P 2 ′ pocket, which is contrary to the binding mode of 1 (derivative lacking ortho isopropyl ester group). In the latter case, benzyl group occupies the P 1 ′ pocket.

6-Phenyl-6-alkylamido-5,6-dihydro-2H-pyran-2-ones: novel HIV protease inhibitors

Abstract Publications from our laboratories have recently described a series of 3-thioaryl substituted-4-hydroxy-pyrones 1 as HIV protease inhibitors. The current work examines the analogous 5,6-dihydro-2H-pyran-2-ones with 6,6-substitutions focusing on the use of 1°, 2°, and 3° alkyl amides of various chain lengths to fill the S1 through S3 enzyme pockets.

Inhibitors of HIV protease: Unique non-peptide active site templates

New templates were designed and prepared which straddle the active site of HIV‐1 protease. These templates were designed to be ‘flexible scaffolds’ upon which substituents could be appended to fill the pockets of HIV protease. The new templates prepared and analysed were 4‐hydroxy‐5H‐furan‐2‐ones, 4‐hydroxy‐5,6‐dihydropyrones, 3‐hydroxy‐cyclohex‐2‐enones, and 4‐hydroxy‐2(1H)‐pyridinones, of which the 4‐hydroxy‐ 5,6‐dihydropyrones were found to be the most potent inhibitors of HIV‐1 protease.