化学
药理学
刺激
地高辛
ATP酶
体内
心力衰竭
作用机理
效力
钙
代谢物
酶
活性代谢物
作者
Andrea Luraghi,Mara Ferrandi,Paolo Barassi,Martina Arici,Shih-Che Hsu,Eleonora Torre,Carlotta Ronchi,Alessio Romerio,Gwo-Jyh Chang,Patrizia Ferrari,Giuseppe Bianchi,Antonio Zaza,Marcella Rocchetti,Francesco Peri
标识
DOI:10.1021/acs.jmedchem.2c00347
摘要
The stimulation of sarcoplasmic reticulum calcium ATPase SERCA2a emerged as a novel therapeutic strategy to efficiently improve overall cardiac function in heart failure (HF) with reduced arrhythmogenic risk. Istaroxime is a clinical-phase IIb compound with a double mechanism of action, Na+/K+ ATPase inhibition and SERCA2a stimulation. Starting from the observation that istaroxime metabolite PST3093 does not inhibit Na+/K+ ATPase while stimulates SERCA2a, we synthesized a series of bioisosteric PST3093 analogues devoid of Na+/K+ ATPase inhibitory activity. Most of them retained SERCA2a stimulatory action with nanomolar potency in cardiac preparations from healthy guinea pigs and streptozotocin (STZ)-treated rats. One compound was further characterized in isolated cardiomyocytes, confirming SERCA2a stimulation and in vivo showing a safety profile and improvement of cardiac performance following acute infusion in STZ rats. We identified a new class of selective SERCA2a activators as first-in-class drug candidates for HF treatment.
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