Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 13; pp. 2949 - 2953
• Main Authors: Takano, Rieko, Yoshida, Masao, Inoue, Masahiro, Honda, Takeshi, Nakashima, Ryutaro, Matsumoto, Koji, Yano, Tatsuya, Ogata, Tsuneaki, Watanabe, Nobuaki, Toda, Narihiro
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.07.2014
• Subjects: Administration, Oral; Animals; Blood Glucose - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; Glucose Tolerance Test; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Propionates - administration & dosage; Propionates - chemistry; Propionates - pharmacology; Rats; Rats, Inbred F344; Rats, Zucker; Receptors, G-Protein-Coupled - agonists; Science & Technology; Structure-Activity Relationship; Agonist; 1 FFA1/GPR40 AGONIST; Insulin secretagogue; INSULIN-SECRETION; RECEPTOR; GPR40; IDENTIFICATION; HUMAN ISLETS; POTENT; Glucose lowering; FREE FATTY-ACIDS; BETA-CELL LINE; SMALL-MOLECULE AGONISTS; Diabetes; TYPE-2 DIABETES-MELLITUS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.04.065

The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic 0 cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia. (C) 2014 Elsevier Ltd. All rights reserved.