Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles
datasetposted on 16.12.2019, 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.
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ETROral Pharmacokinetic ProfilesseriesMetabolic StabilitystabilitystrainWTSafetystainingdifluorobiphenyl moietycytotoxicitiedrug candidate5.6Nondimethylphenyl-DiarylpyrimidineLigand-Based DesignRTassaybioavailabilityhydrochloride formnondimethylphenyl-diarylpyrimidinewater solubilityrat liver microsomesdimethyl analoguesCompound B 13toxicityB 13