A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study

Abstract

Background and purpose: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca²⁺ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.

Experimental approach: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca²⁺ leak via RyR2 and intracellular Ca²⁺ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg^-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.

Key results: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca²⁺ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.

Conclusions and implications: The novel drug M201-A inhibited diastolic Ca²⁺ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Keywords: CCr; CKD; HF; M201‐A; RyR2; eGFR; natriuresis.