Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists
Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists
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DOI：
10.1039/c6ra07356e
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发表时间：
2016-05
期刊：
影响因子：
3.9
通讯作者：
Zheng Li;Jianyong Yang;Weijie Gu;Guoshen Cao;X. Fu;Xuedan Sun;Yu Zhang;Hui Jin;Wen-long Huang;Hai Qian
中科院分区：
文献类型：
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作者：
Zheng Li;Jianyong Yang;Weijie Gu;Guoshen Cao;X. Fu;Xuedan Sun;Yu Zhang;Hui Jin;Wen-long Huang;Hai Qian
游离脂肪酸受体1(FFA1)在促进胰腺β细胞葡萄糖刺激的胰岛素分泌中起着关键作用。大多数报道的FFA1激动剂都含有联苯支架，Daiichi Sankyo证实了这一点与毒性有关。在这里，我们描述了一种非联苯支架的系统探索，以改善GW9508(β-氧化，Fsp3=0.13，tPSA=58.5A2)的药效性。所有这些优化最终导致了化合物21的鉴定，这是一种非传统的激动剂(EC50=72.5 nM)，含有甲肟醚支架。与GW9508(Fsp3=0.13，TPSA=58.5 A2)相比，化合物21具有更好的类药物性质(Fsp3=0.23，TPSA=86.6 A2)，结合效率指数(BEI=15.3)甚至高于TAK-875(BEI=14.3)。进一步的药理学研究表明，化合物21对低血糖风险较低的正常和2型糖尿病小鼠都有相当大的降糖作用。此外，对接研究促进了我们对配体结合口袋的理解。这些信息可能有助于设计更有前途的新分子实体。
The free fatty acid receptor 1 (FFA1) plays a key role in amplifying glucose-stimulated insulin secretion in pancreatic β-cells. Most of the reported FFA1 agonists contain a biphenyl scaffold, which is associated with toxicity as verified by Daiichi Sankyo. Herein, we describe the systematic exploration of a non-biphenyl scaffold to improve the druggability of GW9508 (β-oxidation, Fsp3 = 0.13, tPSA = 58.5 A2) directed by Fsp3 and tPSA values. All these optimizations ultimately led to the identification of compound 21, an unconventional agonist (EC50 = 72.5 nM) bearing a methyl oxime ether scaffold. Moreover, compound 21 revealed improved drug-like properties (Fsp3 = 0.23, tPSA = 86.6 A2) when compared to GW9508 (Fsp3 = 0.13, tPSA = 58.5 A2) and an even higher binding efficiency index (BEI = 15.3) than TAK-875 (BEI = 14.3). Further pharmacological studies suggested that compound 21 has a considerable hypoglycemic effect in both normal and type 2 diabetic mice with a low risk of hypoglycemia. In addition, the docking study promoted our understanding of the ligand-binding pocket. This information might help towards the design of more promising new molecular entities.