Structure-Based Discovery of Novel NH2-Biphenyl-Diarylpyrimidines as Potent Non-Nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Safety: From NH2-Naphthyl-Diarylpyrimidine to NH2-Biphenyl-Diarylpyrimidine

Results from recently completed studies suggested that the NH2-naphthyl-diarylpyrimidine JX-7displayed remarkable inhibitory activity against wild-type HIV-1 (EC50= 5 nM) and numerous clinically observed variants in MT-4 cells; however, its high cytotoxicity (CC50= 19 μM) precluded its further development as a clinical candidate. One approach we took to improve the safety involved replacing the naphthyl of JX-7with biphenyl to provide a series of novel NH2-biphenyl-DAPYs. Investigation of the structure–activity relationships (SARs) led to the identification of 4ab, a potent NNRTI with significantly reduced cytotoxicity (CC50= 120 μM), approximately 6-fold lower than JX-7, which maintained remarkable anti-HIV-1 activity against wild-type HIV-1 (EC50= 1.9 nM) and multiple mutant strains simultaneously. Also, 4abdisplayed weak CYP sensitivity, little inhibition of hERG, and no apparent in vivoacute toxicity. These promising results demonstrate that 4abcan be used as a drug candidate for HIV-1 therapy.