دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease.
المؤلفون: Awasthi BP; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Chaudhary P; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Lim D; Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea., Yadav K; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Lee IH; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Banskota S; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Chaudhary CL; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Karmacharya U; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Lee J; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Im SM; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea., Nam Y; Bio Industry Department, Gyeonggido Business & Science Accelerator, Suwon 16229, Republic of Korea., Eun JW; Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea., Lee S; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea., Lee JM; Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea., Kim ES; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea., Ryou C; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea., Kim TH; Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea., Park HD; Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea., Kim JA; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea., Nam TG; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea., Jeong BS; College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 10601-10621. Date of Electronic Publication: 2024 Jun 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Receptors, G-Protein-Coupled*/antagonists & inhibitors , Receptors, G-Protein-Coupled*/metabolism , Receptors, G-Protein-Coupled*/agonists , Inflammatory Bowel Diseases*/drug therapy , Inflammatory Bowel Diseases*/metabolism , Receptors, Estrogen*/metabolism , Receptors, Estrogen*/antagonists & inhibitors, Humans ; Animals ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/pathology ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Mice ; Molecular Docking Simulation ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/chemical synthesis ; Pyridines/pharmacology ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Pyridines/therapeutic use ; Mice, Inbred C57BL ; Structure-Activity Relationship
مستخلص: 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.
المشرفين على المادة: 0 (Receptors, G-Protein-Coupled)
0 (Receptors, Estrogen)
0 (Interleukin-6)
0 (Tumor Necrosis Factor-alpha)
0 (Anti-Inflammatory Agents)
0 (Pyridines)
0 (GPER1 protein, human)
تواريخ الأحداث: Date Created: 20240619 Date Completed: 20240711 Latest Revision: 20240715
رمز التحديث: 20240715
DOI: 10.1021/acs.jmedchem.3c02458
PMID: 38896548
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c02458