2. Academic Validation
  3. Structure-based design of novel heterocycle-substituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

Structure-based design of novel heterocycle-substituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

  • Acta Pharm Sin B. 2023 Dec;13(12):4906-4917. doi: 10.1016/j.apsb.2023.07.008.
Li-Min Zhao 1 2 3,  Christophe Pannecouque 4,  Erik De Clercq 4,  Shuai Wang 2 3,  Fen-Er Chen 1 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, Yanji 133002, China.
  • 2 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 3 Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 4 Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium.
PMID: 38045058 DOI: 10.1016/j.apsb.2023.07.008
Abstract

Following on our recently developed biphenyl-ATDP non-nucleoside Reverse Transcriptase Inhibitor ZLM-66 (SI = 2019.80, S = 1.9 μg/mL), a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity. Evidently, the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility (SI = 12,497.73, S = 4472 μg/mL) in comparison with ZLM-66 (SI = 2019.80, S = 1.9 μg/mL). This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains (K103N, L100I, Y181C, E138K, and K103N + Y181C). The analog also demonstrated favorable safety and pharmacokinetic profiles, as evidenced by its insensitivity to CYP and hERG, lack of mortality and pathological damage, and good oral bioavailability in rats (F = 27.1%). Further development of 7w for HIV therapy will be facilitated by this valuable information.

Keywords

ATDP; HIV-1; NNRTIs; Pyridone; RT.

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