2. Academic Validation
  3. Discovery of phenylsulfonyl acetic acid derivatives with improved efficacy and safety as potent free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

Discovery of phenylsulfonyl acetic acid derivatives with improved efficacy and safety as potent free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

  • Eur J Med Chem. 2017 Sep 29;138:458-479. doi: 10.1016/j.ejmech.2017.07.001.
Zheng Li 1,  Chunxia Liu 1,  Xue Xu 1,  Qianqian Qiu 1,  Xin Su 1,  Yuxuan Dai 1,  Jianyong Yang 1,  Huilan Li 1,  Wei Shi 1,  Chen Liao 1,  Miaobo Pan 1,  Wenlong Huang 2,  Hai Qian 3
Affiliations

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; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: ydhuangwenlong@126.com.
  • 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: qianhai24@163.com.
PMID: 28689096 DOI: 10.1016/j.ejmech.2017.07.001
Abstract

The Free Fatty Acid Receptor 1 (FFA1) has emerged as an attractive anti-diabetic target that mediates glucose-stimulated Insulin secretion. Several FFA1 agonists have been reported, but many of them possessed somewhat high lipophilicity and/or molecular weight. Herein, we describe the identification of sulfone-carboxylic acid moiety with the multiple advantages of reducing lipophilicity, cytotoxicity and β-oxidation associated with compound 2. Further structure-activity relationship study based on the previleged scaffolds led to the discovery of 2-{(4-[(2'-chloro-[1,1'-biphenyl]-3-yl)methoxy]phenyl)sulfonyl}acetic acid (compound 20), which showed a better balance than compound 2 in terms of physicochemical properties, cytotoxicity profiles and pharmacokinetic properties. Subsequent in vivo studies demonstrated that compound 20 robustly improves the glucose tolerance both in normal and type 2 diabetic models without the risk of hypoglycemia. Compared to the high risk of TAK-875 induced liver toxicity, there was no significant adverse effects such as hepatic and renal toxicity were observed in the chronic toxicity studies of compound 20 even at the higher dose.

Keywords

FFA1; Free fatty acid; Insulin secretion; Type 2 diabetes mellitus.

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