Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists

详细信息    查看全文

• 作者：Zheng Li^a ; Xuekun Wang^a ; ^b ; Xue Xu^c ; Jianyong Yang^a ; Wenting Xia^a ; Xianhao Zhou^a ; Wenlong Huang^a ; ^d ; ^{ydhuangwenlong@126.com" class="auth_mail" title="E-mail the corresponding author} ; Hai Qian^a ; ^d ; ^{qianhai24@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：FFA1 agonist ; Phenoxyacetic acid ; Ligand efficiency ; Type 2 diabetes ; Hypoglycemia
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：23
• 期：22
• 页码：7158-7164
• 全文大小：2439 K

文摘

The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg.