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• W4283725851 endingPage "114581" @default.
• W4283725851 startingPage "114581" @default.
• W4283725851 abstract "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 (EC50 = 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 (T1/2 = 8.45 h), compared to that of doravirine (F = 57%, T1/2 = 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." @default.
• W4283725851 created "2022-07-01" @default.
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• W4283725851 date "2022-10-01" @default.
• W4283725851 modified "2023-09-30" @default.
• W4283725851 title "Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability" @default.
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• W4283725851 doi "https://doi.org/10.1016/j.ejmech.2022.114581" @default.
• W4283725851 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35797898" @default.
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