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

用于治疗高血压和糖尿病的新型 EP 受体拮抗剂

• 批准号: 8597351
• 负责人: RICHARD M. BREYER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597351
• 关键词: Acute; Agonist; Albumins; Albuminuria; Angiotensin II; Animals; Arachidonic Acids; Attenuated; Binding; Biological Assay; Blood Pressure; C57BLKS Mouse; Cardiovascular system; Cells; Chronic Kidney Failure; Comorbidity; Creatinine; Cytochrome P450; Data; Diabetes Mellitus; Diabetic Nephropathy; Dinoprostone; Disease; Dose; Drug Kinetics; EP4 receptor; Genetic; Half-Life; Healthcare; Heart; Hour; Human; Hypertension; In Vitro; Infusion procedures; Kidney; Kidney Diseases; Kidney Failure; Left; Liquid substance; Measures; Mediating; Metabolic; Metabolism; Methods; Mission; Modeling; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oral Administration; Parents; Pathogenesis; Pharmaceutical Preparations; Physiological; Plasma; Population; Predisposition; Progressive Disease; Property; Prostaglandins; Reagent; Regulation; Renal Hypertension; Renal function; Renin-Angiotensin-Aldosterone System; Research; Role; Secondary to; Signal Transduction; Solubility; Testing; Time; United States Department of Veterans Affairs; Urine; Vasoconstrictor Agents; Veterans; Work; analog; aqueous; base; blood pressure regulation; chemical synthesis; human WFDC2 protein; hypertension treatment; in vivo; mortality; mouse model; novel; pressure; prostaglandin EP2 receptor; prostaglandin EP3 receptor; prostanoid receptor EP1; protective effect; public health relevance; radioligand; receptor; response

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. !

描述（由申请人提供）： PGE2 EP1和EP3受体都具有加压剂作用。急性输注受体选择性激动剂会导致平均动脉压增加。此外，EP1的遗传缺失或药理学阻滞减弱了平均动脉压和慢性的平均动脉压的增加。这些数据支持EP1和EP3加压剂受体在直接调节血压以及介导ANG II的压力效应中的作用，因此可能是治疗高血压和糖尿病性肾病（DN）的有用靶标。我们建议开发针对小鼠EP1和EP3受体的药理阻断的试剂，并评估其在DN小鼠模型中的作用，以检验以下假设：EP1和EP3都参与了高血压和糖尿病性肾病的发病机理。为了检验这些假设，将执行以下三个特定目标：在特定的目标1中，将合成EP1和EP3拮抗剂，并在体外进行药理表征。细胞色素P450代谢和水溶性的曲线也将得到优化。在特定的目标2中，将在小鼠中确定这些拮抗剂的体内药代动力学。口服剂量化合物的血浆暴露将随着时间的流逝确定。还将确定体内对血压的急性影响。在特定的目标3中，2型DM和高血压的小鼠模型将用EP1和/或EP3拮抗剂治疗。小鼠将评估血压的变化，以及DM标记的变化，包括蛋白尿，肾功能和肾脏的组织病理学变化，以检查EP受体阻滞在ANG II驱动的高血压模型中的影响。 公共卫生相关性： 描述e豆制（EP）受体在高血压和肾脏损伤中的作用的研究是当前建议的重点。我们的工作假设是，在离开EP2和EP4受体反应完整时，EP1和EP3受体的封锁将在肾脏疾病的环境中具有保护性，并且可能比仅对这些受体中的任何一种或PGE2合成的封锁更有益，这将消除所有前列腺素信号传导。在退伍军人人群中，高血压和慢性肾脏疾病非常普遍，拟议的研究与退伍军人管理高度相关。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的研究任务做出重要贡献，因为它们将应用于高血压和慢性肾脏病的治疗。呢