Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability

Ya-Li Sang; Christophe Pannecouque; Erik De Clercq; Shuai Wang; Fen-Er Chen

Acta Pharmaceutica Sinica B (Jul 2023)

Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability

Ya-Li Sang,
Christophe Pannecouque,
Erik De Clercq,
Shuai Wang,
Fen-Er Chen

Affiliations

Ya-Li Sang: Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; School of Science, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, 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
Shuai Wang: Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Corresponding authors.
Fen-Er Chen: Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; School of Science, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, China; Corresponding authors.

Journal volume & issue: Vol. 13, no. 7
pp. 3054 – 3066

Abstract

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Considering the undesirable metabolic stability of our recently identified NNRTI 5 (t1/2 = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes (t1/2 = 2754 min), which was about 29-fold longer than that of 5 (t1/2 = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC50 = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC50 = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound 9g was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.

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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