2. Academic Validation
  3. Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases

Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases

  • Eur J Med Chem. 2022 Nov 15;242:114631. doi: 10.1016/j.ejmech.2022.114631.
Haobai Liu 1,  Quan Wang 2,  Yue Huang 2,  Jinhui Deng 1,  Xi Xie 3,  Jiaqi Zhu 1,  Yijun Yuan 4,  Yue-Ming He 1,  Yi-You Huang 5,  Hai-Bin Luo 6,  Xixin He 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya, 572000, China.
  • 5 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR China; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya, 572000, China. Electronic address: [email protected].
  • 6 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR China; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya, 572000, China. Electronic address: [email protected].
  • 7 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China. Electronic address: [email protected].
PMID: 35985255 DOI: 10.1016/j.ejmech.2022.114631
Abstract

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 Inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.

Keywords

Inflammatory Bowel Diseases; Mangostanin; PDE4 inhibitor; Safety.

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