691897-84-4Relevant academic research and scientific papers
Design, synthesis, and biological activity of potent and orally available g protein-coupled receptor 40 agonists
Sasaki, Shinobu,Kitamura, Shuji,Negoro, Nobuyuki,Suzuki, Masami,Tsujihata, Yoshiyuki,Suzuki, Nobuhiro,Santou, Takashi,Kanzaki, Naoyuki,Harada, Masataka,Tanaka, Yasuhiro,Kobayashi, Makoto,Tada, Norio,Funami, Miyuki,Tanaka, Toshimasa,Yamamoto, Yoshio,Fukatsu, Kohji,Yasuma, Tsuneo,Momose, Yu
, p. 1365 - 1378 (2011/05/05)
G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic β-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC50 = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-2- fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC50 = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.
Structure-activity study of dihydrocinnamic acids and discovery of the potent FFA1 (GPR40) agonist TUG-469
Christiansen, Elisabeth,Due-Hansen, Maria E.,Urban, Christian,Merten, Nicole,Pfleiderer, Michael,Karlsen, Kasper K.,Rasmussen, Sanne S.,Steensgaard, Mette,Hamacher, Alexandra,Schmidt, Johannes,Drewke, Christel,Petersen, Rasmus Koefoed,Kristiansen, Karsten,Ullrich, Susanne,Kostenis, Evi,Kassack, Matthias U.,Ulven, Trond
scheme or table, p. 345 - 349 (2010/12/19)
The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).
RECEPTOR FUNCTION CONTROLLING AGENT
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Page/Page column 90, (2008/06/13)
The GPR40 receptor function regulator of the present invention, which comprises a compound having an aromatic ring and a group capable of releasing cation is useful as an insulin secretagogue or an agent for the prophylaxis or treatment of diabetes and the like.
