Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment

  • J Med Chem. 2024 Feb 27. doi: 10.1021/acs.jmedchem.3c01524.
Gaofeng Lin  1  2 ,  Qinlong Xu  2 ,  Jiaming Li  1  3  4 ,  Zhaoxing Chu  2 ,  Xiaodong Ma  1  3  4 ,  Qihua Zhu  5 ,  Yan Zhao  2 ,  Jiajia Mo  2 ,  Wenfeng Ye  2 ,  Li Shao  2 ,  Tao Fang  2 ,  Minghan He  6 ,  Shaoyun Yue  2 ,  Mingqi Dai  2
Affiliations
  • 1. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 2. Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei 230088, China.
  • 3. Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China.
  • 4. Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei 230012, China.
  • 5. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 6. Rutgers Preparatory School, Somerset, New Jersey 08873, United States.
PMID: 38413367 DOI: 10.1021/acs.jmedchem.3c01524
Abstract

A series of structurally novel GluN2B NMDAR antagonists were designed, synthesized, and biologically evaluated as anti-stroke therapeutics by optimizing the chemical structure of Pierardine, the active ingredient of traditional Chinese medicine Dendrobium aphyllum (Roxb.) C. E. Fischer identified via in silico screening. The systematic structure-activity relationship study led to the discovery of 58 with promising NMDAR-GluN2B binding affinity and antagonistic activity. Of the two enantiomers, S-58 exhibited significant inhibition (IC50 = 74.01 ± 12.03 nM) against a GluN1/GluN2B receptor-mediated current in a patch clamp assay. In addition, it displayed favorable specificity over Other subtypes and off-target receptors. In vivo, S-58 exerted therapeutic efficacy comparable to that of the approved GluN2B NMDAR antagonist ifenprodil and excellent safety profiles. In addition to the attractive in vitro and in vivo potency, S-58 exhibited excellent brain exposure. In light of these merits, S-58 has been advanced to further preclinical investigation as a potential anti-stroke candidate.

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