Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists
Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists
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DOI：
10.1021/acs.jmedchem.3c01923
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发表时间：
2024-02-21
影响因子：
7.3
通讯作者：
Ulven，Trond
中科院分区：
文献类型：
--
作者：
Ieremias，Loukas;Kaspersen，Mads H.;Ulven，Trond
GPR 84是一种公认的中链脂肪酸受体，参与炎症和纤维化的调节。研究表明，GPR 84激动剂可能在阿尔茨海默病、动脉粥样硬化和癌症等疾病中具有治疗潜力，但缺乏高质量的工具化合物来探索这种潜力。脂肪酸类似物LY 237（4a）是迄今为止公开的最有效的GPR 84激动剂，但具有不利的物理化学性质。我们在这里提出了一个SAR研究4a。几个高度有效的激动剂被确定与EC 50低至28 pM，与SAR通常在基于结构的建模非常一致。通过适当引入环和极性基团，鉴定出TUG-2099（4s）和TUG-2208（42 a），这两种高效GPR 84激动剂具有较低的亲脂性和良好至优异的溶解性、体外渗透性和微粒体稳定性，这将是探索GPR 84药理学和治疗前景的有价值的工具。
GPR84 is a putative medium-chain fatty acid receptor that is implicated in regulation of inflammation and fibrogenesis. Studies have indicated that GPR84 agonists may have therapeutic potential in diseases such as Alzheimer’s disease, atherosclerosis, and cancer, but there is a lack of quality tool compounds to explore this potential. The fatty acid analogue LY237 (4a) is the most potent GPR84 agonist disclosed to date but has unfavorable physicochemical properties. We here present a SAR study of4a. Several highly potent agonists were identified with EC50down to 28 pM, and with SAR generally in excellent agreement with structure-based modeling. Proper incorporation of rings and polar groups resulted in the identification of TUG-2099 (4s) and TUG-2208 (42a), both highly potent GPR84 agonists with lowered lipophilicity and good to excellent solubility, in vitro permeability, and microsomal stability, which will be valuable tools for exploring the pharmacology and therapeutic prospects of GPR84.