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: 8242614
• 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/8242614
• 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）：