Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

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• 作者：Zheng Li^a ; Miaobo Pan^a ; Xin Su^a ; Yuxuan Dai^a ; Mian Fu^a ; Xingguang Cai^a ; Wei Shi^a ; Wenlong Huang^a ; ^b ; ^{ydhuangwenlong@126.com" class="auth_mail" title="E-mail the corresponding author} ; Hai Qian^a ; ^b ; ^{qianhai24@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：FFA1 agonist ; GPR40 ; Ligand efficiency ; Type 2 diabetes ; Pyrrole
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：24
• 期：9
• 页码：1981-1987
• 全文大小：2150 K

文摘

The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound class="boldFont">11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.