jm9b01446_si_002.csv (3.48 kB)
Download file

Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles

Download (3.48 kB)
posted on 2019-12-16, 16:27 authored by Yali Sang, Sheng Han, Christophe Pannecouque, Erik De Clercq, Chunlin Zhuang, Fener Chen
A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 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.