Abstract 121: The Selective Aldosterone Synthase Inhibitor PB6440 Normalizes Blood Pressure In A Human Aldosterone Synthase-Transgenic Mouse Model Of Hypertension

Abstract

Introduction: Aldosterone synthase inhibitors are emerging as important future treatment options for diseases associated with aldosterone signaling, such as resistant hypertension and chronic renal disease. PB6440 is a potent inhibitor of aldosterone synthase (CYP11B2) with high selectivity over the closely related enzyme CYP11B1. The goal of the current study was to determine whether PB6440 was capable of reducing aldosterone production and blood pressure in an established human aldosterone synthase-transgenic mouse strain (hAS +/- ) that is associated with aldosterone excess and the development of hypertension under a 4% salt diet. Methods: hAS +/- mice were administered PB6440, positive controls and vehicle by oral gavage. In a single-dose study, plasma aldosterone levels were assessed 8 hours after the administration of PB6440 at 2, 10 and 30 mg/kg as well as the positive control fadrozole at 5 mg/kg. In a pilot study, blood pressure was assessed following 10 days of PB6440 once daily at 10 mg/kg as well as the positive control spironolactone at 50 mg/kg. In a definitive study, blood pressure was assessed following 8 weeks of PB6440 once daily at 30 mg/kg as well as spironolactone at 50 mg/kg. Blood pressure was assessed 4-6 hours after drug dosing using a tail-cuff system. Results: In the single-dose study, PB6440 markedly reduced plasma aldosterone with a similar potency to fadrozole (e.g., PB6440 10 mg/kg -96% compared to vehicle; fadrozole 5 mg/kg -96%). In the pilot study, PB6440 normalized both systolic and diastolic blood pressures to that of wild-type mice, with a somewhat greater effect on both parameters than spironolactone at day 10. In the definitive study, PB6440 normalized both systolic and diastolic blood pressures to that of wild-type mice through 8 weeks with an efficacy similar to spironolactone. The decreases in SBP were approximately 30 mm Hg and DBP approximately 20 mm Hg in both drug groups compared to vehicle-treated hAS +/- mice. Conclusions: PB6440 was shown to lower aldosterone levels and normalize blood pressure through 8 weeks in an established mouse model of aldosterone excess and hypertension. PB6440 is a promising potential therapy for the treatment of conditions associated with aldosterone signaling in humans.