Improving Druggability of Novel Diarylpyrimidine NNRTIs by a Fragment-Based Replacement Strategy: From Biphenyl-DAPYs to Heteroaromatic-Biphenyl-DAPYs

A series of novel heteroaromatic-difluoro-biphenyl-diarylpyrimidines
were designed as non-nucleoside anti-HIV inhibitors targeting reverse
transcriptase by a fragment-based replacement strategy with the purpose
of improving the druggability. Hopping five- or six-membered heterocycle
groups on the biphenyl moiety as bioisosterism for intrinsically cyanophenyl
gave 23 derivatives. All of these compounds possessed excellent HIV-1
inhibitory activity in the nanomolar range. Among them, 12g with a 4-pyridine group displayed excellent inhibitory activity
toward WT and mutant HIV virus possessing significant selectivity.
Moreover, this compound exhibited a decent improvement in druggability
than etravirine and rilpivirine: (1) The hydrochloric acid salt of 12g exhibited significantly improved water solubility in different
pH conditions. (2) 12g did not show apparent CYP enzymatic
inhibitory activity or acute toxicity. (3) Excellent oral bioavailability
was also revealed (F = 126%, rats) in 12g. Collectively, these novel heteroaromatic-biphenyl-DAPYs represent
promising drug candidates for HIV clinical therapy.