Identification of a Potent and Selective Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist with Favorable Physicochemical and in Vitro ADME Properties
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- 作者：Elisabeth Christiansen ; Christian Urban ; Manuel Grundmann ; Maria E. Due-Hansen ; Ellen Hagesaether ; Johannes Schmidt ; Leonardo Pardo ; Susanne Ullrich ; Evi Kostenis ; Matthias Kassack ; Trond Ulven
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：October 13, 2011
- 年：2011
- 卷：54
- 期：19
- 页码：6691-6703
- 全文大小：1156K
- 年卷期：v.54,no.19(October 13, 2011)
- ISSN：1520-4804
文摘
The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic 尾-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.