Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

The prostaglandin E2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life and low aqueous solubility, which renders them sub-optimal for testing in animal models of disease. We now report a novel compound TG8–69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases including rheumatoid arthritis, endometriosis and cancer, in which EP2 appears to play a pathogenic role.

前列腺素E2受体EP2在生理学以及多种病理状况中发挥着重要作用。研究表明，在慢性外周和中枢神经系统疾病以及癌症模型中，EP2具有促炎作用。因此，用小分子靶向EP2受体可能是治疗炎症性疾病和癌症的一种治疗策略。我们最近报道了一类新型的EP2受体竞争性拮抗剂。然而，早期的先导化合物对DP1前列腺素受体选择性较低，血浆半衰期适中，水溶性低，这使得它们在疾病动物模型中测试时并非最佳选择。我们现在报道一种新型化合物TG8 - 69，它具有合适的类药性质。我们介绍了该化合物的合成、先导化合物优化研究、药理学特性以及抗炎特性，这些都支持其用于包括类风湿性关节炎、子宫内膜异位症和癌症在内的慢性外周炎症性疾病，在这些疾病中EP2似乎起着致病作用。