Design, synthesis and biological activity of deuterium-based FFA1 agonists with improved pharmacokinetic profiles
Design, synthesis and biological activity of deuterium-based FFA1 agonists with improved pharmacokinetic profiles
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具有改善药代动力学特征的氘基 FFA1 激动剂的设计、合成和生物活性
DOI：
10.1016/j.bmcl.2019.04.019
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发表时间：
2019
影响因子：
2.7
通讯作者：
Li Zheng
中科院分区：
文献类型：
--
作者：
Liu Bing;Deng Liming;Chen Haidong;Liao Ruoxian;Li Yuyi;Zeng Xiaohua;Deng Fengjian;Zhang Luyong;Li Zheng
游离脂肪酸受体1（free fatty acid receptor 1，FFA 1）是一种具有葡萄糖刺激胰岛素分泌功能的抗糖尿病靶点。先前报道的化合物2是一种高效的FFA 1激动剂，但由于苯丙酸易被β-氧化，因此其可能具有较差的药代动力学性质。为了鉴定口服可用的类似物，我们试图通过在苯基丙酸部分掺入氘来阻断β-氧化途径。正如预期的那样，氘基类似物3和4表现出比母体化合物2更好的药代动力学性质。化合物2和3的降糖效果差异不大，但氘类似物3的降糖效果优于化合物2。同时，化合物3与TAK-875的结合口袋对接良好，在结合位点形成与TAK-875几乎相同的相互作用。与格列本脲不同，即使在60 mg/kg的高剂量下，在化合物3中观察到低血糖症的风险较低。
The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound2is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analogs, we tried to block the route of β-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs3and4exhibited better pharmacokinetic properties than parent compound2. Although the difference of potency between compound2and3is quite small, the glucose-lowering effect of deuterium analog3was better than that of compound2. Meanwhile, compound3docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound3even at the high dose of 60 mg/kg.