Development of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors:Boosting the safety and metabolic stability  

作　　者：Xin Jin Shuai Wang Limin Zhao Wenjuan Huang Yinxiang Zhang Christophe Pannecouque Erik De Clercq Ge Meng Huri Piao Fener Chen 

机构地区：[1]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [2]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China [3]Key Laboratory of Natural Resources of Changbai Mountain&Functional Molecules,Ministry of Education,College of Pharmacy,Yanbian University,Yanji 133002,China [4]Rega Institute for Medical Research,KU Leuven,Leuven B-3000,Belgium

出　　处：《Acta Pharmaceutica Sinica B》2023年第3期1192-1203,共12页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(Nos.21871055 and 22077018)'National Key R&D Program of China(2017YFA0506000).

摘　　要：Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(EC_(50)=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(CC_(50)=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 NH_(2)-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain(EC_(50)=1.8–349 nmol/L).The best compound 5t in this collection(EC_(50)=1.8 nmol/L,CC_(50)=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)=74.52 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.

关 键 词：HIV-1 NNRTI DAPYs SAFETY Metabolic stability 

分 类 号：TQ460.1[化学工程—制药化工]