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

描述（由申请人提供）： PGE2 EP1和EP3受体均具有血管升压作用；急性输注受体选择性激动剂会导致平均动脉压升高。此外，EP1 的基因缺失或药理学阻断可短期和长期减弱 Ang II 依赖性平均动脉压的增加。这些数据支持 EP1 和 EP3 血管加压受体在直接调节血压以及部分介导 Ang II 升压作用方面的作用，因此可能成为治疗高血压和糖尿病肾病 (DN) 的有用靶标。我们建议开发药物阻断小鼠 EP1 和 EP3 受体的试剂，并评估其在 DN 小鼠模型中的作用，以检验 EP1 和 EP3 均参与高血压和糖尿病肾病发病机制的假设。为了测试这些假设，将执行以下三个具体目标： 在具体目标 1 中，将在体外合成 EP1 和 EP3 拮抗剂并进行药理学表征。细胞色素 P450 代谢和水溶性的概况也将得到优化。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。将测定小鼠体内随时间推移的口服化合物的血浆暴露量。还将确定对血压的急性体内影响。在具体目标 3 中，2 型糖尿病和高血压的小鼠模型将用 EP1 和/或 EP3 拮抗剂治疗。将评估小鼠的血压变化以及糖尿病标志物的变化，包括蛋白尿、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： 描述 E-前列腺素 (EP) 受体在高血压和肾损伤中的作用的研究是当前提案的重点。我们的工作假设是，在肾脏疾病的情况下，同时阻断 EP1 和 EP3 受体，同时保持 EP2 和 EP4 受体反应完整，将具有保护作用，并且可能比单独阻断这些受体中的任何一个或阻断 PGE2 合成更有益，后者会消除所有前列腺素信号传导。高血压和慢性肾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，并为退伍军人管理局的研究任务做出重要贡献，因为它们将应用于高血压和慢性肾脏疾病的治疗。 ！

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. !