Development of second generation EP2 antagonists with high selectivity.
Development of second generation EP2 antagonists with high selectivity.
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DOI：
10.1016/j.ejmech.2014.05.076
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发表时间：
2014-07-23
影响因子：
6.7
通讯作者：
Dingledine R
中科院分区：
文献类型：
--
作者：
Ganesh T;Jiang J;Dingledine R
EP 2受体已成为治疗干预的重要生物靶点。特别是，它已被证明会加剧各种CNS和外周疾病的疾病进展。小鼠模型中EP 2受体的缺失概括了考克斯-2抑制的几个特征，从而提供了一种新的抗炎治疗途径，其可以绕过考克斯-2抑制治疗观察到的一些不良副作用。我们最近报道了肉桂酰胺类的EP 2拮抗剂具有高效力，但这些化合物对前列腺素受体DP 1表现出中等的选择性。此外，它们在结构中具有丙烯酰胺部分，这可能导致在慢性疾病模型中长期使用的肝毒性。因此，我们现在开发了第二代化合物，其不含丙烯酰胺官能团，并且具有高效力和相对于其他前列腺素类受体对EP 2的改善的（>1000倍）选择性。
EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors.
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