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

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

Acta Pharmaceutica Sinica B (Mar 2023)

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

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

Affiliations

Xin Jin: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China
Shuai Wang: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
Limin Zhao: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China
Wenjuan Huang: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
Yinxiang Zhang: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
Christophe Pannecouque: Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
Erik De Clercq: Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
Ge Meng: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Corresponding authors. Tel./fax: +86 21 65643811.
Huri Piao: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China; Corresponding authors. Tel./fax: +86 21 65643811.
Fener Chen: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China; Corresponding authors. Tel./fax: +86 21 65643811.

Journal volume & issue: Vol. 13, no. 3
pp. 1192 – 1203

Abstract

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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.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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