Identification of a Potent and Selective Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist with Favorable Physicochemical and in Vitro ADME Properties

被引：60

作者：

Christiansen, Elisabeth ^{[1
]}

Urban, Christian ^{[2
]}

Grundmann, Manuel ^{[3
]}

Due-Hansen, Maria E. ^{[1
]}

Hagesaether, Ellen ^{[1
]}

Schmidt, Johannes ^{[3
]}

Pardo, Leonardo ^{[4
]}

Ullrich, Susanne ^{[5
]}

Kostenis, Evi ^{[3
]}

Kassack, Matthias ^{[2
]}

Ulven, Trond ^{[1
]}

机构：

[1] Univ So Denmark, Dept Chem & Phys, DK-5230 Odense M, Denmark

[2] Univ Dusseldorf, Inst Pharmaceut & Med Chem, D-40225 Dusseldorf, Germany

[3] Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany

[4] Univ Autonoma Barcelona, Fac Med, Unitat Bioestat, Lab Med Computac, E-08193 Barcelona, Spain

[5] Univ Tubingen, Div Endocrinol Diabetol & Clin Chem, Dept Internal Med, D-72076 Tubingen, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 19期

关键词：

PROTEIN-COUPLED RECEPTOR; PANCREATIC BETA-CELLS; INSULIN-SECRETION; SMALL-MOLECULE; DRUG DISCOVERY; GPR40; AGONIST; ANTAGONISTS; GLUCOSE; MICE; STIMULATION;

D O I：

10.1021/jm2005699

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic beta-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

引用

页码：6691 / 6703

页数：13

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