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

Zheng Li; Xuekun Wang; Xue Xu; Jianyong Yang; Wenting Xia; Xianhao Zhou; Wenlong Huang; Hai Qian

doi:10.1016/j.bmc.2015.10.011

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

Bioorg Med Chem. 2015 Nov 15;23(22):7158-64. doi: 10.1016/j.bmc.2015.10.011. Epub 2015 Oct 8.

Authors

Zheng Li¹, Xuekun Wang², Xue Xu³, Jianyong Yang¹, Wenting Xia¹, Xianhao Zhou¹, Wenlong Huang⁴, Hai Qian⁵

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² 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.
³ Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
⁴ 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: [email protected].
⁵ 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: [email protected].

PMID: 26482570
DOI: 10.1016/j.bmc.2015.10.011

Abstract

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.

Keywords: FFA1 agonist; Hypoglycemia; Ligand efficiency; Phenoxyacetic acid; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetates / chemical synthesis
Acetates / chemistry*
Acetates / therapeutic use
Animals
Binding Sites
CHO Cells
Calcium / metabolism
Cricetinae
Cricetulus
Diabetes Mellitus, Type 2 / drug therapy
Drug Design*
Glucose Tolerance Test
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / therapeutic use
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Molecular Docking Simulation
Protein Structure, Tertiary
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Structure-Activity Relationship

Substances

Acetates
FFAR1 protein, human
Hypoglycemic Agents
Receptors, G-Protein-Coupled
Calcium
phenoxyacetic acid