Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability


Acta Pharmaceutica Sinica B


Sang, Y. L., Pannecouque, C., De Clercq, E., Wang, S., & Chen, F. E. (2023). Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability. Acta Pharmaceutica Sinica B.



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.

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