Deuteration Strategy-Inspired Design of Novel Diarylpyrimidine Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Improved Efficacy, Selectivity, and Druggability

Deuteration strategy holds significant importance in the field of drug development. In this study, the deuteration strategy was applied to incorporate deuterated methyl groups at the metabolic sites where methyl groups were originally present, with the expectation of improving the anti-HIV activity, safety, and druggability. Among the deuterated compounds, the exemplary compound 5a (ZK-316) exhibited potent and broad-spectrum activity against wild-type and clinically observed mutant strains, with EC₅₀ values ranging from 0.99 to 75.1 nM, surpassing that of the hit compound 3 (EC₅₀ = 1.86-795.76 nM). Moreover, low cytotoxicity was exhibited by ZK-316 (CC₅₀ > 225 nM), which was over 36.8 times lower than that of compound 3, and high selectivity was also shown. Not only was there no apparent inhibition of cytochrome P450 (CYP) enzymes, but also low human ether-à-go-go-related gene (hERG) toxicity was found. And favorable pharmacokinetic profiles were shown as well, with a bioavailability of 29%, all of which indicated its promising druggability. Additionally, the identification of the metabolites of ZK-316 was carried out to verify the stability of the deuterated methyl groups within human liver microsomes. These results offer valuable insights into the development of deuterated non-nucleoside reverse transcriptase inhibitors (NNRTIs) for human immunodeficiency virus (HIV) therapy.