Anti-hypertensive Effect of a Novel Angiotensin II Receptor Neprilysin Inhibitor (ARNi) -S086 in DSS rat model

Background: and Purpose: Angiotensin receptor-NEP inhibitor (ARNi), which is consisting of an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating hypertension. S086 is a novel ARNi cocrystal developed by Salubris for the treatment of heart failure and hypertension. Rat hypertension model and telemetry system were used in our study to investigate circadian rhythm of rat blood pressure and evaluate the anti-hypertensive efficacy of S086. Experimental Approach: Dahl Salt Sensitive (DSS) hypertensive rat model and telemetry system were used in this research. Key Results: Our findings revealed the circadian rhythm of DSS rat blood pressure was opposite to that of humans, with high blood pressure occurring during the night. Oral administration of S086 dose-dependently lowered the blood pressure and exhibited better efficacy than LCZ696, particularly 16-24h after dosing. No significant changes were observed on water consumption, natriuresis and diuresis among all high salt groups. Conclusion: This paper demonstrates the ability of anti-hypertensive effect of S086 in preclinic and supports the product to conduct phase 2/3 clinical trial. Implications: This study reveals circadian rhythm of DSS rat blood pressure and provides the anti-hypertensive efficacy of S086 to support the further clinical study.