Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist
| Autor: | Julio C. Medina, Jonathan B. Houze, Xianyun Jiao, Liusheng Zhu, Ying Sun, Vatee Pattaropong, Paul John Dransfield, Marc Vimolratana, Simon Wong, Frank Li, Qi Guo, Jinqian Liu, Jane Zhang, Jian Luo, Run Zhuang, Gayathri Swaminath, Daniel C.-H. Lin, Sean P. Brown |
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| Rok vydání: | 2012 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty medicine.drug_class business.industry Pancreatic islets Organic Chemistry Pharmacology Hypoglycemia medicine.disease Biochemistry Partial agonist Endocrinology medicine.anatomical_structure In vivo Internal medicine Free fatty acid receptor 1 Drug Discovery medicine Inverse agonist Receptor business |
| Zdroj: | ACS Medicinal Chemistry Letters. 3:726-730 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/ml300133f |
| Popis: | GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1. |
| Databáze: | OpenAIRE |
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