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

Veterans Health Administration, Decatur PA

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Abstract

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.