Novel EP receptor antagonists for the treatment of hypertension and of diabetes

描述（由申请人提供）： PGE 2 EP 1和EP 3受体均具有血管加压作用;急性输注受体选择性激动剂可导致平均动脉压升高。此外，EP 1的基因缺失或药物阻断减弱了急性和慢性平均动脉压的Ang II依赖性增加。这些数据支持EP 1和EP 3血管加压素受体在直接调节血压以及部分介导Ang II的升压作用中的作用，因此可能是治疗高血压和糖尿病肾病（DN）的有用靶点。我们建议开发用于药理学阻断小鼠EP 1和EP 3受体的试剂，并评估其在DN小鼠模型中的作用，以检验EP 1和EP 3均参与高血压和糖尿病肾病发病机制的假设。为了检验这些假设，将进行以下三个特定目的：在特定目的1中，将合成EP 1和EP 3拮抗剂并在体外进行生物学表征。还将优化细胞色素P450代谢和水溶性的特征。在具体目标2中，将在小鼠中测定这些拮抗剂的体内药代动力学。将在小鼠中随时间测定经口给药化合物的血浆暴露。还将确定对血压的急性体内影响。在具体目标3中，将使用EP 1和/或EP 3拮抗剂治疗2型DM和高血压小鼠模型。将评估小鼠的血压变化和DM标志物（包括白蛋白尿）的变化、肾功能以及肾脏和心脏的组织病理学变化，以检查EP受体阻断在Ang II驱动的高血压模型中的作用。 公共卫生相关性： 研究描绘的作用，E-前列腺素（EP）受体在高血压和肾损害是目前的建议的重点。我们的工作假设是，阻断EP 1和EP 3受体，同时保持EP 2和EP 4受体反应完整，将在肾脏疾病的情况下具有保护作用，并且可能比单独阻断这些受体中的任一种或阻断PGE 2合成（其将消除所有前列腺素信号传导）更有益。高血压和慢性肾脏疾病在退伍军人群体中非常普遍，拟议的研究与退伍军人管理局高度相关。我们预计，本申请中提出的研究将对退伍军人的医疗保健产生重大影响，并为VA的研究使命做出重要贡献，因为它们将用于治疗高血压和慢性肾脏疾病。!

DESCRIPTION (provided by applicant): Both the PGE2 EP1 and EP3 receptors have vasopressor actions; acute infusion of receptor-selective agonists causes increased mean arterial pressure. In addition, genetic deletion or pharmacological blockade of EP1 attenuates the Ang II-dependent increase in mean arterial pressure both acutely and chronically. These data support a role for EP1 and EP3 vasopressor receptors in directly modulating blood pressure as well as mediating, in part, the pressor effects of Ang II, and therefore could be useful targets for the treatment of hypertension and diabetic nephropathy (DN). We propose to develop reagents for pharmacological blockade of the mouse EP1 and EP3 receptors and assess their effects in mouse models of DN to test the hypothesis that both EP1 and EP3 are involved in the pathogenesis of hypertension and diabetic nephropathy. To test these hypotheses the following three Specific Aims will be performed: In Specific Aim 1, EP1 and EP3 antagonists will be synthesized and pharmacologically characterized in vitro. Profiles of cytochrome P450 metabolism and aqueous solubility will also be optimized. In Specific Aim 2, the in vivo pharmacokinetics of these antagonists will be determined in mice. Plasma exposure of orally dosed compounds will be determined over time in mice. Acute in vivo effects on blood pressure will also be determined. In Specific Aim 3, Mouse models of type 2 DM and hypertension will be treated with EP1 and/or EP3 antagonists. Mice will assessed for changes in blood pressure, and changes in markers of DM including albuminuria, renal function and histopathological changes in the kidney and the heart to examine the effects of EP receptor blockade in Ang II driven models of hypertension. PUBLIC HEALTH RELEVANCE: Studies delineating the role of E-prostanoid (EP) receptors in hypertension and renal damage are the focus of the current proposal. Our working hypothesis is that blockade of both the EP1 and EP3 receptors while leaving the EP2 and EP4 receptor response intact will be protective in settings of renal disease and may be more beneficial than blockade of either of these receptors alone, or blockade of PGE2 synthesis, which would abrogate all prostaglandin signaling. Hypertension and chronic kidney disease are very prevalent in the Veteran population, and the proposed studies are highly relevant to the Veterans Administration. We anticipate that the studies proposed in this application will have significant impact on Veterans' health care and make important contributions to the research mission of the VA as they will be applied the treatment of hypertension and chronic kidney disease. !