Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists: Mesylpropoxy Appendage Lowers Lipophilicity and Improves ADME Properties

被引：47

作者：

Christiansen, Elisabeth ^{[1
]}

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

Urban, Christian ^{[2
]}

Grundmann, Manuel ^{[3
]}

Schroeder, Ralf ^{[3
]}

Hudson, Brian D. ^{[4
]}

Milligan, Graeme ^{[4
]}

Cawthorne, Michael A. ^{[5
]}

Kostenis, Evi ^{[3
]}

Kassack, Matthias U. ^{[2
]}

Ulven, Trond ^{[1
]}

机构：

[1] Univ So Denmark, Dept Phys Chem & Pharm, 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 Glasgow, Mol Pharmacol Grp, Inst Mol Cell & Syst Biol, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland

[5] Univ Buckingham, Clore Lab, Buckingham MK18 1EG, Bucks, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 14期

关键词：

BIOAVAILABLE GPR40 AGONIST; SMALL-MOLECULE AGONISTS; INSULIN-SECRETION; DISCOVERY; POTENT; IDENTIFICATION; CELLS; EFFICIENCY; GLUCOSE;

D O I：

10.1021/jm3002026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on S. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13.

引用

页码：6624 / 6628

页数：5

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