Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability

被引：46

作者：

Christiansen, Elisabeth ^{[1
]}

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

Urban, Christian ^{[2
]}

Grundmann, Manuel ^{[3
]}

Schmidt, Johannes ^{[3
]}

Hansen, Steffen V. F. ^{[1
]}

Hudson, Brian D. ^{[4
]}

Zaibi, Mohamed ^{[5
]}

Markussen, Stine B. ^{[1
]}

Hagesaether, Ellen ^{[1
]}

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, Coll Med Vet & Life Sci, Inst Mol Cell & Syst Biol, Glasgow G12 8QQ, Lanark, Scotland

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 03期

关键词：

SMALL-MOLECULE AGONISTS; INSULIN-SECRETION; GPR40; AGONIST; ADME PROPERTIES; DRUG DISCOVERY; CELLS; IDENTIFICATION; GLUCOSE; ANTAGONISTS; EFFICIENCY;

D O I：

10.1021/jm301470a

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) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.

引用

页码：982 / 992

页数：11

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