Development of fluorine-substituted NH2-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability.
10.1016/j.apsb.2022.08.017
- Author:
Xin JIN
1
;
Shuai WANG
1
;
Limin ZHAO
1
;
Wenjuan HUANG
1
;
Yinxiang ZHANG
1
;
Christophe PANNECOUQUE
2
;
Erik DE CLERCQ
2
;
Ge MENG
1
;
Huri PIAO
3
;
Fener CHEN
1
Author Information
1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
2. Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium.
3. Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China.
- Publication Type:Journal Article
- Keywords:
DAPYs;
HIV-1;
Metabolic stability;
NNRTI;
Safety
- From:
Acta Pharmaceutica Sinica B
2023;13(3):1192-1203
- CountryChina
- Language:English
-
Abstract:
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 (t 1/2 = 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 (t 1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t 1/2 = 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.
