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

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.