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首页> 外文期刊>RSC Advances >Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists
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Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists

机译：发现一种新型肟醚支架作为有效和口服生物可利用的游离脂肪酸受体1激动剂

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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, F _(sp ~(3) ) = 0.13, tPSA = 58.5 ? ~(2) ) directed by F _(sp ~(3) ) and tPSA values. All these optimizations ultimately led to the identification of compound 21 , an unconventional agonist (EC _(50) = 72.5 nM) bearing a methyl oxime ether scaffold. Moreover, compound 21 revealed improved drug-like properties ( F _(sp ~(3) ) = 0.23, tPSA = 86.6 ? ~(2) ) when compared to GW9508 ( F _(sp ~(3) ) = 0.13, tPSA = 58.5 ? ~(2) ) 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.
机译：游离脂肪酸受体1（FFA1）在扩增胰腺β细胞中扩增葡萄糖刺激的胰岛素分泌的关键作用。大多数报道的FFA1激动剂含有双苯基支架，其与Daiichi Sankyo验证的毒性有关。在此，我们描述了对非联苯支架的系统探索，以改善GW9508的可解离性（β-氧化，F _（SP〜（3））= 0.13，TPSA = 58.5？〜（2））（ SP〜（3））和TPSA值。所有这些优化最终导致了化合物21的鉴定，一种携带甲基肟醚支架的非传统激动剂（EC _（50）= 72.5nm）。此外，与GW9508（F _（SP〜（3））= 0.13，TPSA相比，化合物21显示出改善的药物状性质（F _（SP〜（3））= 0.23，TPSA = 86.6〜（2）） = 58.5？〜（2））和比TWA-875（BEI = 14.3）更高的绑定效率指数（BEI = 15.3）。进一步的药理学研究表明，化合物21在正常和2型糖尿病小鼠中具有相当大的降血糖作用，具有低血糖风险的风险低。此外，对接研究促进了我们对配体绑定口袋的理解。这些信息可能有助于设计更有前途的新分子实体。

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