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

• Published in: Acta pharmaceutica Sinica. B 2023-03, Vol.13 (3), p.1192-1203
• Main Authors: Jin, Xin, Wang, Shuai, Zhao, Limin, Huang, Wenjuan, Zhang, Yinxiang, Pannecouque, Christophe, De Clercq, Erik, Meng, Ge, Piao, Huri, Chen, Fener
• Format: Article
• Language: English
• Subjects: DAPYs; HIV-1; Metabolic stability; NNRTI; Original; Safety
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2022.08.017

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t1/2 = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 μmol/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 = 1.8–349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 μmol/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 (t1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t1/2 = 14.6 min). Also, 5t possessed good stability in both human and monkey plasma. No significant in vitro 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. In the present study, we reported a series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable anti-HIV activity, of which 5t exhibited significantly improved druggability. [Display omitted]