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  3. Novel bis(triazole) analogues as selective TGR5 agonists with anti-diabesity effects

Novel bis(triazole) analogues as selective TGR5 agonists with anti-diabesity effects

  • Bioorg Chem. 2026 Jan:168:109286. doi: 10.1016/j.bioorg.2025.109286.
Anchal Saxena 1,  Devanshu Kaushik 2,  Boda Arun Kumar 2,  Shivam Rathaur 3,  Diwan Chand 4,  Kinshuk R Srivastava 4,  Jiaur R Gayen 5,  Prem N Yadav 6,  Nayan Ghosh 7
Affiliations

Affiliations

  • 1 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Jawaharlal Nehru University (JNU), New Delhi 110067, India.
  • 2 Neuroscience and Ageing Biology Division, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Jawaharlal Nehru University (JNU), New Delhi 110067, India.
  • 3 Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Jawaharlal Nehru University (JNU), New Delhi 110067, India.
  • 4 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India.
  • 5 Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India.
  • 6 Neuroscience and Ageing Biology Division, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India. Electronic address: pn.yadav@cdri.res.in.
  • 7 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, U.P. 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India. Electronic address: nayan.ghosh@cdri.res.in.
PMID: 41337824 DOI: 10.1016/j.bioorg.2025.109286
Abstract

The TGR5 receptor (or GP-BAR1) was discovered as the first G protein-coupled receptor (GPCR) that specifically binds bile acids. TGR5 is considered a potential target for the treatment of metabolic disorders, including type 2 diabetes. In the quest for the discovery of novel antidiabetic compounds, a series of 31 bis(triazole) derivatives were synthesized and evaluated over TGR5 for agonist activity. We found that compound 5a had modest TGR5 agonist activity at the human TGR5 receptor. This prompted us to synthesise several modifications of 5a to obtain compounds with better TGR5 agonist's affinity and efficacy. We discovered three novel derivatives 7b, 7i and 8h using rational design and molecular docking, followed by the evaluation at the TGR5 receptor for agonist activity. The compound with the highest potency, 7i, exhibited an EC50 of 571 ± 89 nM. The pharmacokinetic study with 7i in mice (30 mg/kg, i.p.) showed Cmax of 3920 ± 1236 ng/mL and half-life (T1/2) 2.91 h. We further determined the in vivo effect of 7i on blood glucose and food intake, and found that 7i (30 mg/kg; i.p.) significantly reduced blood glucose and food intake in acute studies, and reduced weight gain in chronically treated Db/Db mice. Furthermore, 7i did not exhibit any cytotoxicity up to 10 μM. Together with emerging evidence of TGR5's role in pain and mood disorders and our own findings on obesity, supports the further development and optimization of 7i as a therapeutic TGR5 agonist for diabetes and obesity.

Keywords

Bile acid receptor agonist; Bis(triazole) analogs; Diabetes; GloSensor assay; Obesity.

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