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<sub>50</sub> = 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<sub>1/2</sub> = 8.45 h), compared to that of doravirine (F = 57%, T<sub>1/2</sub> = 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.