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

Rieko Takano; Masao Yoshida; Masahiro Inoue; Takeshi Honda; Ryutaro Nakashima; Koji Matsumoto; Tatsuya Yano; Tsuneaki Ogata; Nobuaki Watanabe; Narihiro Toda

doi:10.1016/j.bmcl.2014.04.065

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

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2949-53. doi: 10.1016/j.bmcl.2014.04.065. Epub 2014 Apr 26.

Authors

Affiliations

¹ R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
² R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].

PMID: 24835985
DOI: 10.1016/j.bmcl.2014.04.065

Abstract

The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β 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.

Keywords: Agonist; Diabetes; GPR40; Glucose lowering; Insulin secretagogue.

MeSH terms

Administration, Oral
Animals
Blood Glucose / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Glucose Tolerance Test
Humans
Molecular Structure
Propionates / administration & dosage
Propionates / chemistry
Propionates / pharmacology*
Rats
Rats, Inbred F344
Rats, Zucker
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Blood Glucose
FFAR1 protein, human
G-protein-coupled receptor 40, rat
Propionates
Receptors, G-Protein-Coupled
propionic acid