2. Academic Validation
  3. Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

  • Bioorg Med Chem. 2015 Oct 15;23(20):6666-72. doi: 10.1016/j.bmc.2015.09.010.
Zheng Li 1,  Xuekun Wang 1,  Xue Xu 2,  Jianyong Yang 1,  Qianqian Qiu 1,  Hao Qiang 1,  Wenlong Huang 3,  Hai Qian 4
Affiliations

Affiliations

  • 1 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3 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.
  • 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: qianhai24@163.com.
PMID: 26420383 DOI: 10.1016/j.bmc.2015.09.010
Abstract

The Free Fatty Acid Receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.

Keywords

Amide linkers; FFA1 agonist; Ligand efficiency; OGTT; Type 2 diabetes.

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