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: 8391565
• 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/8391565
• 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.

描述(由申请人提供)： PGE2、EP1和EP3受体都有升压作用；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的基因缺失或药物阻断可显著或长期减轻依赖血管紧张素II的平均动脉压升高。这些数据支持EP1和EP3升压受体在直接调节血压中的作用，以及部分介导Ang II的升压作用，因此可能成为治疗高血压和糖尿病肾病(DN)的有用靶点。我们建议开发药物阻断小鼠EP1和EP3受体的试剂，并评估它们在小鼠糖尿病肾病模型中的作用，以检验EP1和EP3都参与高血压和糖尿病肾病发病机制的假设。为了验证这些假设，将执行以下三个特定目标：在特定目标1中，将合成EP1和EP3拮抗剂，并在体外进行药理学表征。细胞色素P450的代谢和水的溶解度也将得到优化。在特定目标2中，将测定这些拮抗剂在小鼠体内的药代动力学。口服化合物的血浆暴露将随着时间的推移而在小鼠身上确定。对血压的急性体内影响也将被确定。在具体目标3中，将用EP1和/或EP3拮抗剂治疗2型糖尿病和高血压的小鼠模型。将评估小鼠的血压变化和糖尿病标志物的变化，包括蛋白尿、肾功能和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效果。