26165-64-0Relevant academic research and scientific papers
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
Li, Zheng,Liu, Chunxia,Xu, Xue,Qiu, Qianqian,Su, Xin,Dai, Yuxuan,Yang, Jianyong,Li, Huilan,Shi, Wei,Liao, Chen,Pan, Miaobo,Huang, Wenlong,Qian, Hai
, p. 458 - 479 (2017/07/10)
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.
Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
Li, Zheng,Pan, Miaobo,Su, Xin,Dai, Yuxuan,Fu, Mian,Cai, Xingguang,Shi, Wei,Huang, Wenlong,Qian, Hai
supporting information, p. 1981 - 1987 (2016/04/20)
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.
Novel nitrogen-containing heterocyclic derivative and preparation method thereof and application of derivative by serving as drug
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Paragraph 0131-0133; 0134, (2017/02/24)
The invention relates to a novel nitrogen-containing heterocyclic derivative shown as a general formula (I) (please see the formula in the description) and a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating diabetes and a metabolic syndrome. The nitrogen-containing heterocyclic derivative has the excellent in-vivo hypoglycemic activity and can be used for preventing or treating the diabetes.
