Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability.

Adding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66 , which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (EC 50 = 13 nM) and various single/double mutant strains. ZLM-66 possessed acceptable cytotoxicity and selectivity index. In vivo profiling indicated that ZLM-66 exhibited excellent pharmacokinetics with significantly improved oral bioavailability (F = 140.24%) and a more favorable half-life (T 1/2 = 8.45 h), compared to that of doravirine (F = 57%, T 1/2 = 4.4 h). In addition, ZLM-66 did not cause significant inhibition of CYP and hERG (>200 μM), as well as acute toxicity and tissue damage at a dose of 1.2 g/kg. Therefore, ZLM-66 can be used as a lead compound to further guide the development of orally active biphenyl-containing doravirine analogs for HIV therapy. [Display omitted] • Novel biphenyl-substituted pyridone derivatives were rationally designed as potent NNRTIs. • ZLM-66 displayed significant inhibitory activity against WT HIV-1 and multiple mutant strains. • ZLM-66 exhibited promising oral availability (F = 140.24%). • ZLM-66 showed almost no CYP enzyme and hERG inhibition. • No acute toxicity and pathological damage were observed at a dose of 1.2 g/kg. [ABSTRACT FROM AUTHOR]