4-Hydroxy-5,6-dihydropyrones. 2. Potent Non-Peptide Inhibitors of HIV Protease

Abstract

The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the aim of filling S1 and S2 and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S2. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P2 and P2'. Parent dihydropyrone 1c (IC50 = 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC50 = 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio] -2H-pyran-2-yl)pentanoic acid and 12c, IC50 = 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3- [(2-phenyl-ethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S1' and S2' afforded potent HIV protease inhibitor 49 [IC50 = 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6-dihydro-4 -hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (< 475) have one or no chiral centers and are readily synthesized.

Prediction of HIV-1 protease inhibitory activity of 4-hydroxy-5,6-dihydropyran-2-ones: QSAR study

“…In the present work we have taken 59 4-hydroxy-5,6-dihydropyran-2-one compounds (Table 1) and their HIV-1 protease inhibitory activity from the reported work 17 . All the HIV-1 protease inhibitory activities used in the present study were expressed as pIC 50 = −log 10 IC 50 ; where IC 50 is the micro molar concentration of the compounds producing 50% reduction in the HIV-1 protease activity is stated as the means of at least two experiments.…”

“…The present group of authors has developed a few quantitative structure-activity relationship models to predict biological activity of different group of compounds [10][11][12][13][14][15][16] . In continuation of such efforts, in this article, we have performed QSAR analysis for HIV-1 protease inhibitory activity of 4-hydroxy-5, 6-dihydropyran-2-one derivatives 17 using modelling software WIN CAChe 6.1 (molecular modelling software) and statistical software STATISTICA 6.…”

Structure-based discovery of tipranavir disodium (PNU-140690E): A potent, orally bioavailable, nonpeptidic HIV protease inhibitor

“…Initial studies 37 were directed toward the 5,6-dihydropyrone template and mirrored efforts being advanced on the pyrone nucleus. Separate studies 42,43 in other labs have also focused on this ring system. Simple analogues 37 such as compound 16 could be prepared that were structurally similar to the related pyrones and displayed comparable enzymatic inhibitory activity (Figure 7).…”

Modification and biological evaluation of novel 4-hydroxy-pyrone derivatives as non-peptidic HIV-1 protease inhibitors

“…Different research groups have synthesized series of 4-hydroxy-pyran-2-one derivatives as HIV-1 PR inhibitors (Romines and Chrusciel, 1995;Vara Prasad et al, 1999;Tummino et al, 1996;Thaisrivongs et al, 1996;Lunney et al, 1994;Skulnick et al, 1995;Tait et al, 1997;Sun et al, 2005). The pyran-2-one group, 4-hydroxyl group, and substitution at the 3-position were all necessary for the HIV-1 PR inhibitory activity.…”