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

Abstract

AbstractBackground and PurposeThe 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 ApproachFollowing 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 ResultsIn 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 ImplicationsThe 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.