Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant : Lead identification and SAR of 3- and 4-substituted derivatives

Through computationally directed broad screening, a novel 1,5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC50 = 2.3 μM) and delavirdine-resistant P236L (IC50 = 1.1 μM) reverse transcriptase (RT). Also, PNU-32945 has an ED50 for inhibition of viral replication in cell cultures of 0.1 μM and was shown to be noncytotoxic with a CC50 > 10 μM. Structure−activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC50 = 0.65 μM), whereas it is essentially inactive versus the wild-type enzyme (IC50 > 50 μM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.