PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
J Med Chem. 2013 Jun 27;56(12):5182-97. doi: 10.1021/jm400587g. Epub 2013 Jun 17.
8-Amido-chromen-4-one-2-carboxylic acid derivatives were identified as novel agonists at the G protein-coupled orphan receptor GPR35. They were characterized by a β-arrestin recruitment assay and optimized to obtain agonists with nanomolar potency for the human GPR35. The compounds were found to exhibit high selectivity versus the related GPR55. The most potent agonists were 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (85, EC50 12.1 nM) and 6-bromo-8-(2-chloro-4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (90, EC50 11.1 nM), both of which were >1700-fold selective versus GPR55. Most compounds were considerably less potent at rat and mouse than at human GPR35. 6-Bromo-8-(2-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (87) was the only derivative that activated GPR35 of all three species at similar, low micromolar concentration. Compounds 85 and 90 are the most potent agonists at the human GPR35 known to date and might thus serve as powerful pharmacological tools to further elucidate the receptor's (patho)physiological role and its potential as a future drug target.
8-酰胺基香豆素-4-酮衍生物被鉴定为 G 蛋白偶联孤儿受体 GPR35 的新型激动剂。它们通过β-arrestin 募集测定进行了表征，并进行了优化，以获得对人 GPR35 具有纳摩尔效力的激动剂。这些化合物被发现对相关的 GPR55 具有高选择性。最有效的激动剂是 6-溴-8-(4-甲氧基苯甲酰胺基)-4-氧代-4H-色烯-2-羧酸（85，EC50 为 12.1 nM）和 6-溴-8-(2-氯-4-甲氧基苯甲酰胺基)-4-氧代-4H-色烯-2-羧酸（90，EC50 为 11.1 nM），两者对 GPR55 的选择性均>1700 倍。大多数化合物在大鼠和小鼠中的效力均明显低于人 GPR35。6-溴-8-(2-甲氧基苯甲酰胺基)-4-氧代-4H-色烯-2-羧酸（87）是唯一一种在所有三种物种中以相似的低微摩尔浓度激活 GPR35 的衍生物。化合物 85 和 90 是迄今为止在人 GPR35 中最有效的激动剂，因此可能成为强大的药理学工具，以进一步阐明受体的（病理）生理作用及其作为未来药物靶点的潜力。
