Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
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DOI：
10.1021/acs.jmedchem.8b00855
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发表时间：
2018-11-08
影响因子：
7.3
通讯作者：
Ulven, Trond
中科院分区：
文献类型：
--
作者：
Hansen, Anders Hojgaard;Sergeev, Eugenia;Ulven, Trond
游离脂肪酸受体2（FFA 2/GPR 43）是短链脂肪酸的受体，据报道其参与调节代谢、食欲、脂肪积累和炎症反应，并且是用于治疗各种炎症和代谢疾病的潜在靶标。通过用合成上更易处理的噻唑烷生物电子等排置换先前公开的FFA 2激动剂的中心吡咯烷核心，我们能够快速合成和筛选在噻唑烷核心上的2-和3-位处修饰的类似物。在本文中，我们报告了噻唑烷FFA 2激动剂的SAR探索和31（TUG-1375）的鉴定，该化合物相对于吡咯烷先导结构具有显著增加的效力（在cAMP测定中为7倍）和亲脂性降低（clogP降低50倍）。该化合物具有高溶解度、高化学、微粒体和肝细胞稳定性以及有利的药代动力学特性，并被证实可诱导人中性粒细胞动员并抑制鼠脂肪细胞中的脂解。
Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.