Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469

被引：55

作者：

Christiansen, Elisabeth ^{[1
]}

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

Urban, Christian ^{[2
]}

Merten, Nicole ^{[3
]}

Pfleiderer, Michael ^{[4
]}

Karlsen, Kasper K. ^{[1
]}

Rasmussen, Sanne S. ^{[1
]}

Steensgaard, Mette ^{[1
]}

Hamacher, Alexandra ^{[2
]}

Schmidt, Johannes ^{[3
]}

Drewke, Christel ^{[3
]}

Petersen, Rasmus Koefoed ^{[5
]}

Kristiansen, Karsten ^{[5
]}

Ullrich, Susanne ^{[4
]}

Kostenis, Evi ^{[3
]}

Kassack, Matthias U. ^{[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, Dept Mol Cellular & Pharmacobiol, D-53115 Bonn, Germany

[4] Univ Tubingen, Dept Internal Med, Div Endocrinol Diabetol Vasc Med Nephrol & Clin C, D-72076 Tubingen, Germany

[5] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen N, Denmark

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 07期

关键词：

Diabetes; FFA1; FFAR1; GPR40; fatty acids; drug discovery; SMALL-MOLECULE AGONISTS; PANCREATIC BETA-CELLS; SECRETION IN-VIVO; FREE FATTY-ACIDS; INSULIN-SECRETION; RECEPTOR GPR40; MICE; GLUCOSE; PHARMACOLOGY; STIMULATION;

D O I：

10.1021/ml100106c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic beta-cells and amplifies glucose-stimulated insulin secretion, has emerged as 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).

引用

页码：345 / 349

页数：5

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