Development of fluorine-substituted NH2-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability.

Abstract

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50=1.0nmol/L), but the poor metabolic stability in human liver microsomes (t 1/2=14.6min) and insufficient selectivity (SI=2059) with high cytotoxicity (CC50=2.08μmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain (EC50=1.8-349nmol/L). The best compound 5t in this collection (EC50=1.8nmol/L, CC50=117μmol/L) was 32-fold in selectivity (SI=66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t 1/2=74.52min), approximately 5-fold higher than JK-4b in human liver microsomes (t 1/2=14.6min). Also, 5t possessed good stability in both human and monkey plasma. No significant invitro inhibition effect toward CYP enzyme and hERG was observed. The single-dose acute toxicity test did not induce mice death or obvious pathological damage. These findings pave the way for further development of 5t as a drug candidate.