Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK

A series of novel heteroaromatic
biphenyl-methyl-pyrimidine analogues
were designed via hybridization of privileged structures of two HIV-1
inhibitors. Among them, compound 7a containing 4-pyridinyl-phenyl
and methyl-pyrimidine fragments revealed excellent wild-type HIV-1
inhibitory activity with low cytotoxicity. 7a had favorable
solubility and liver microsome stability; moreover, no apparent CYP
enzymatic inhibitory activity or acute toxicity was observed. However,
its inhibitory activity toward mutant strains and the pharmacokinetic
(PK) profiles were still unsatisfactory. Further optimizations resulted
in a highly potent compound 9d without methyl on the
pyrimidine but a heteroaromatic dimethyl-biphenyl on the left rings
of difluoro-pyridinyl-diarylpyrimidines (DAPYs). A broad-spectrum
activity (EC50 = 2.0–57 nM) of 9d against
resistant strains was revealed. This compound also exhibited good
solubility and safety profiles and a good PK profile with an oral
bioavailability of 59% in rats. Collectively, these novel heteroaromatic
dimethyl-biphenyl-DAPYs represent promising drug candidates for HIV
clinical therapy.