Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine.,Bioorganic & Medicinal Chemistry Letters

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Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-01-17 , DOI: 10.1016/j.bmcl.2019.01.014
Deyu Kong ₁ , Shimeng Guo ₂ , Yushe Yang ₃ , Bin Guo ₃ , Xin Xie ₂ , Wenhao Hu ₄

Affiliation

FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.

中文翻译：

新型有效的含2,3-二氢苯并[b] [1,4]二恶英的FFA1激动剂的合成和生物学评估。

FFA1（游离脂肪酸受体1）已成为一种有吸引力的抗糖尿病靶标，因为它在低血糖风险低的胰腺β细胞中介导葡萄糖刺激的胰岛素分泌的增强作用。许多报道的FFA1激动剂具有一定的药代动力学和/或安全性问题。在这里，我们描述了2,3-二氢苯并[b] [1,4]二恶英作为FFA1激动剂的新型支架的鉴定。基于这种支架的全面的构效关系研究导致发现了（S）-3-（4-（（（（S）-7-（4-methoxyphenyl）-2,3-dihydrobenzo] [b] [1,4 ]二恶英-2-基）甲氧基）苯基）己基-4-炔酸（26k），它显示出强大的FFA1激动活性和良好的药代动力学特征。随后的体内研究表明，化合物26k可显着改善ICR小鼠的葡萄糖耐量。总之，

更新日期：2019-01-17

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