Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.
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.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Zheng
Z
Li
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, PR China.
Xuekun
X
Wang
Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Xue
X
Xu
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Jianyong
J
Yang
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Wenting
W
Xia
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Xianhao
X
Zhou
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: ydhuangwenlong@126.com.
Wenlong
W
Huang
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.
Hai
H
Qian
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000085:Acetates; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D002118:Calcium; C415326:phenoxyacetic acid
FFA1 agonist; Hypoglycemia; Ligand efficiency; Phenoxyacetic acid; Type 2 diabetes