4.7 Article

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

期刊

BIOORGANIC & MEDICINAL CHEMISTRY
卷 24, 期 9, 页码 1981-1987

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.03.014

关键词

FFA1 agonist; GPR40; Ligand efficiency; Type 2 diabetes; Pyrrole

资金

  1. National Natural Science Foundation of China [81172932, 81273376]
  2. Natural Science Foundation of Jiangsu Province [BK2012356]
  3. Fundamental Research Funds for the Central Universities, China Pharmaceutical University [JKZD2013001]

向作者/读者索取更多资源

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 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. (C) 2016 Elsevier Ltd. All rights reserved.

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