2. Academic Validation
  3. G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease

G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease

  • J Med Chem. 2024 Jul 11;67(13):10601-10621. doi: 10.1021/acs.jmedchem.3c02458.
Bhuwan Prasad Awasthi 1,  Prakash Chaudhary 1,  Dongchul Lim 2,  Kiran Yadav 1,  Iyn-Hyang Lee 1,  Suhrid Banskota 1,  Chhabi Lal Chaudhary 1,  Ujjwala Karmacharya 1,  Jiwoo Lee 1,  So Myoung Im 3,  YeonJu Nam 4,  Ji Won Eun 5,  Sungeun Lee 3,  Ji-Min Lee 6,  Eun Soo Kim 7,  Chongsuk Ryou 3,  Tae Hun Kim 2,  Hee Dong Park 2,  Jung-Ae Kim 1,  Tae-Gyu Nam 3,  Byeong-Seon Jeong 1
Affiliations

Affiliations

  • 1 College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
  • 2 Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea.
  • 3 Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea.
  • 4 Bio Industry Department, Gyeonggido Business & Science Accelerator, Suwon 16229, Republic of Korea.
  • 5 Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea.
  • 6 Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
  • 7 Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
PMID: 38896548 DOI: 10.1021/acs.jmedchem.3c02458
Abstract

Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using in silico methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled Estrogen Receptor 1 (GPER) as the molecular target for the most effective analogue, 6-26, which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity. This was further validated by surface plasmon resonance (SPR) assay results, which showed direct binding to GPER, and by the results showing that GPER knockdown abolished the inhibitory effects of 6-26 on TNFα and IL-6 actions. Notably, 6-26 displayed no cytotoxicity, unlike G1 and G15, a well-known GPER agonist and an antagonist, respectively, which induced Necroptosis independently of GPER. These findings suggest that the GPER-selective compound 6-26 holds promise as a therapeutic candidate for IBD.

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