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

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

  • Eur J Med Chem. 2022 Oct 5;240:114581. doi: 10.1016/j.ejmech.2022.114581.
Li-Min Zhao 1,  Shuai Wang 2,  Christophe Pannecouque 3,  Erik De Clercq 3,  Hu-Ri Piao 4,  Fen-Er Chen 5
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, 977 Gongyuan Road, Yanji, Jilin Province, 133002, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
  • 2 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
  • 3 Rega Institute for Medical Research, KU Leuven, Herestraat 49, B, 3000, Leuven, Belgium.
  • 4 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, 977 Gongyuan Road, Yanji, Jilin Province, 133002, China. Electronic address: piaohr@ybu.edu.cn.
  • 5 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, 977 Gongyuan Road, Yanji, Jilin Province, 133002, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: rfchen@fudan.edu.cn.
PMID: 35797898 DOI: 10.1016/j.ejmech.2022.114581
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.

Keywords

Doravirine; HIV-1; NNRTIs; Oral bioavailability.

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