4-hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: The effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters

Due largely to the emergence of multi-drug-resistant HIV strains, the devel opment of new HIV protease inhibitors remains a high priority for the pharm aceutical industry. Toward this end, we previously identified a 4-hydroxy-5 ,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activ ity against the protease enzyme, good antiviral efficacy in cellular assays , and promising bioavailability in several animal species. The search for a suitable backup candidate centered on the replacement of the aniline moiet y at C-6 with an appropriately substituted heterocyle. In general, this ser ies of heterocyclic inhibitors displayed good activity (in both enzymatic a nd cellular tests) and-low cellular toxicity; furthermore, several analogue s exhibited improved pharmacokinetic parameters in animal models. The compo und with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tertbutyl-4-hydroxymethy1- 5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-on e (13-(S)). This thiophene derivative also exhibited excellent antiviral ef ficacy against mutant HIV protease and resistant HIV strains. For these rea sons, compound 13-(S) was chosen for further preclinical evaluation.