166953-80-6Relevant articles and documents
Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold
Li, Zheng,Ren, Qiang,Wang, Xuekun,Zhou, Zongtao,Hu, Lijun,Deng, Liming,Guan, Li,Qiu, Qianqian
, (2019)
Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.
Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists
Wang, Xuekun,Zhao, Tianxiao,Yang, Baowei,Li, Zheng,Cui, Jian,Dai, Yuxuan,Qiu, Qianqian,Qiang, Hao,Huang, Wenlong,Qian, Hai
, p. 132 - 140 (2015/02/18)
Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50 = 62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.
NOVEL COMPOUNDS, THEIR PREPARATION AND USE
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Page/Page column 67; 68, (2008/06/13)
Novel compounds of the general formula (I), the use of these compounds as phar- maceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds are activators of PPARδ and should be useful for treating conditions mediated by the same.
