Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability
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- 作者：Elisabeth Christiansen ; Maria E. Due-Hansen ; Christian Urban ; Manuel Grundmann ; Johannes Schmidt ; Steffen V. F. Hansen ; Brian D. Hudson ; Mohamed Zaibi ; Stine B. Markussen ; Ellen Hagesaether ; Graeme Milligan ; Michael A. Cawthorne ; Evi Kostenis ; Matthias U. Kassack ; Trond Ulven
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：56
- 期：3
- 页码：982-992
- 全文大小：588K
- 年卷期：v.56,no.3(February 14, 2013)
- ISSN：1520-4804
文摘
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鈥揳ctivity 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.