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

Li-Min Zhao; Shuai Wang; Christophe Pannecouque; Erik De Clercq; Hu-Ri Piao; Fen-Er Chen

doi:10.1016/j.ejmech.2022.114581

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. Epub 2022 Jun 30.

Authors

Li-Min Zhao¹, Shuai Wang², Christophe Pannecouque³, Erik De Clercq³, Hu-Ri Piao⁴, Fen-Er Chen⁵

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 (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.

Keywords: Doravirine; HIV-1; NNRTIs; Oral bioavailability.

MeSH terms

Anti-HIV Agents* / chemistry
Biological Availability
Biphenyl Compounds
HIV Reverse Transcriptase / metabolism
Pyridones / chemistry
Pyridones / pharmacology
Reverse Transcriptase Inhibitors* / chemistry
Reverse Transcriptase Inhibitors* / pharmacology
Structure-Activity Relationship

Substances

Anti-HIV Agents
Biphenyl Compounds
Pyridones
Reverse Transcriptase Inhibitors
diphenyl
HIV Reverse Transcriptase