4-Hydroxy-5,6-dihydropyrones as Inhibitors of HIV Protease:  The Effect of Heterocyclic Substituents at C-6 on Antiviral Potency and Pharmacokinetic Parameters

Abstract

Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.

The 4D-QSAR Paradigm: Application to a Novel Set of Non-peptidic HIV Protease Inhibitors

“…Such a set of compound was reported by Hagen and colleagues [21]. These researchers have prepared and tested a set of 38 analogs [21].…”

“…Such a set of compound was reported by Hagen and colleagues [21]. These researchers have prepared and tested a set of 38 analogs [21]. We, however, chose to construct 4D-QSAR models using only those compounds showing both nanomolar enzyme inhibition potency, expressed in IC 50 (nM), and the toxicity in cells in the absence of virus measures, expressed in TC 50 (mM) [21].…”

Elucidating the Inhibiting Mode of AHPBA Derivatives against HIV-1 Protease and Building Predictive 3D-QSAR Models

“…9 More recent advances in inhibitor design have focused on structural modification to improve their inhibitory potency and oral bioavailability and to circumvent drug resistances. [10][11][12][13] Despite these successes, it is nearly impossible to treat all of the growing worldwide AIDS population based on currently available drugs, so the need for inexpensive and widely available HIVPR inhibitors still exists.…”

Polymer‐Supported Bisacetoxybromate(I) Anion –‐An Efficient Co‐Oxidant in the TEMPO‐Mediated Oxidation of Primary and Secondary Alcohols

“…Where necessary, flash column chromatography was performed on silica gel 60 (230 ± 400 mesh). Except for alcohols 18,20,22,24,26,28,30,34,36, and 38 all starting compounds are commercially available. Alcohols 22, 24, and 26 were prepared from commercial (2R)-3-hydroxy-2-methylpropionic methyl ester by standard protection of the alcohol group and dibalpromoted reduction of the ester functionality under standard conditions.…”

“…Aldehydes and ketones 8, 11, 13, 15, 17, 43, 45, 47, 49 and 51 are known and are commercially available. The spectroscopic and physical data of aldehydes and ketones 19, [33] 21, [36] 23, [34] 37, [37] 39 [38] and 41 [39] are listed in the literature.…”