极性芳环外周增加了灵感来自 LY2881835 的螺环游离脂肪酸受体 (GPR40) 激动剂的激动剂效力。
Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835.
机构信息
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation.
Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86 Vernadskogo Prospekt, Moscow, 117571 Russian Federation.
出版信息
Eur J Med Chem. 2017 Feb 15;127:357-368. doi: 10.1016/j.ejmech.2017.01.005. Epub 2017 Jan 4.
A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus.
受礼来公司处于一期临床的抗糖尿病游离脂肪酸 1 型受体激动剂 LY2881835 的启发，我们设计了一系列螺环化合物，旨在引入极性芳香基团，并探索在激动剂结合部位附近与靶标形成额外结合的可能性。该系列的先导化合物（9i）对游离脂肪酸 1 型受体具有很强的活性（EC₅₀=260nM），在生理相关的缓冲液（PBS）中溶解度高，Caco-2 渗透率良好。通过对接研究对观察到的构效关系进行了合理化解释。该新系列显著扩展了配体结构多样性，旨在寻找新型高效、更极性的游离脂肪酸 1 型受体激动剂，作为针对 2 型糖尿病的全新治疗药物类别。
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