基于配体的非二甲苯基二芳基嘧啶的设计，改善了代谢稳定性、安全性和口服药代动力学特征。
Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles.
机构信息
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry , Fudan University , Shanghai 200433 , People's Republic of China.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , Shanghai 200433 , People's Republic of China.
出版信息
J Med Chem. 2019 Dec 26;62(24):11430-11436. doi: 10.1021/acs.jmedchem.9b01446. Epub 2019 Dec 16.
A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of exhibited an improved water solubility of 5.6 μg/mL compared with ETR (≪1 μg/mL), better stability in human and rat liver microsomes, and a great oral bioavailability of 44%, making it promising as a drug candidate. In addition, no apparent toxicity was observed in the acute toxicity assay (2 g/kg) and HE staining.
我们开发了一系列比其二甲苯基类似物毒性低得多的非二甲基苯基二苯并嘧啶。带有二氟联苯部分的化合物 对 WT、突变株和 RT 显示出最高的抗病毒活性。盐酸盐形式的 与 ETR（≪1 μg/mL）相比，具有 5.6 μg/mL 的改善的水溶性，在人肝和大鼠肝微粒体中更稳定，口服生物利用度高达 44%，有望成为候选药物。此外，在急性毒性试验（2 g/kg）和 HE 染色中未观察到明显的毒性。
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