Pharmacodynamic and pharmacokinetic effects of S086, a novel angiotensin receptor neprilysin inhibitor

• Main Authors: Jingchao Sun, Wenjie Xu, Huaijie Hua, Ying Xiao, Xiaoyan Chen, Zhiwei Gao, Song Li, Xiaolong Jing, Frank Du, Guofeng Sun
• Format: Article
• Language: English
• Published: Elsevier 2020-09-01
• Series: Biomedicine & Pharmacotherapy
• Subjects: Angiotensin receptor-NEP inhibitor; Heart failure; Neprilysin inhibitor; Angiotensin receptor blocker
• Online Access: http://www.sciencedirect.com/science/article/pii/S075333222030603X

Background and Purpose: Angiotensin receptor-NEP inhibitor (ARNi), which includes an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating heart failure with reduced ejection fraction (HF-REF). S086 is a novel single-molecule ARNi that includes the molecular moieties of EXP3174 (the active metabolite of the ARB losartan) and sacubitril (a NEP inhibitor prodrug) in a 1:1 M ratio. We performed preclinical animal model studies to evaluate the efficacy of S086 in treating HF. Experimental Approach: Rat and dog models of myocardial ischemia-induced chronic heart failure were used in this research. Principal Results: The oral administration of S086 dose-dependently lowered the heart weight index, attenuated cardiac fibrosis, and improved left ventricular ejection fraction, shortening fraction, and cardiac output, without effects on hemodynamics in animal models of myocardial ischemia-induced chronic heart failure. A comparable protective effect to LCZ696 was observed for S086 at an equal molar dose in dog models. In addition, S086 was superior to LCZ696 since it significantly reversed the decrease in left ventricular posterior wall end-systolic thickness. Conclusion: This animal study suggests that S086 is effective in treating myocardial ischemia-induced chronic heart failure.