Issue 11, 2023

Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability

Abstract

Interfering with the assembly of hepatitis B virus (HBV) capsid is a promising approach for treating chronic hepatitis B (CHB). In order to enhance the metabolic stability and reduce the strong hERG inhibitory effect of HBV capsid assembly modulator (CAM) GLS4, we rationally designed a series of carboxyl-containing heteroaryldihydropyrimidine (HAP) derivatives based on structural biology information combined with medicinal chemistry strategies. The results from biological evaluation demonstrated that compound 6a-25 (EC50 = 0.020 μM) exhibited greater potency than the positive drug lamivudine (EC50 = 0.09 μM), and was comparable to the lead compound GLS4 (EC50 = 0.007 μM). Furthermore, it was observed that 6a-25 reduced levels of core protein (Cp) and capsid in cells. Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 μg mL−1; pH 7.0: 6.85 μg mL−1; pH 7.4: 25.48 μg mL−1), liver microsomal metabolic stability (t1/2 = 108.2 min), and lower hERG toxicity (10 μM inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation.

Graphical abstract: Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability

Supplementary files

Article information

Article type
Research Article
Submitted
03 Sep 2023
Accepted
30 Sep 2023
First published
18 Oct 2023

RSC Med. Chem., 2023,14, 2380-2400

Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability

S. Zhao, Y. Wang, X. Zhang, L. Qiao, S. Wang, Y. Jin, S. Wu, Y. Li, P. Zhan and X. Liu, RSC Med. Chem., 2023, 14, 2380 DOI: 10.1039/D3MD00461A

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