Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469
Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469
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DOI：
10.1021/ml100106c
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发表时间：
2010-10-01
影响因子：
4.2
通讯作者：
Ulven, Trond
中科院分区：
文献类型：
--
作者：
Christiansen, Elisabeth;Due-Hansen, Maria E.;Ulven, Trond
游离脂肪酸1受体（FFA 1或GPR 40）在胰腺β细胞上高度表达并放大葡萄糖刺激的胰岛素分泌，已成为治疗2型糖尿病的有吸引力的靶点。已知几种含有对位取代的二氢肉桂酸部分的FFA 1激动剂。在这里，我们提出了一个结构-活性关系的研究，这个化合物的家庭表明，中央亚甲基氧基连接器是优选的较小的化合物，而中央亚甲基胺连接器提供更高的效力较大的化合物。该研究发现了有效和选择性的完全FFA 1激动剂TUG-469（29）。
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).