Discovery of Reldesemtiv, a Fast Skeletal Muscle Troponin Activator for the Treatment of Impaired Muscle Function

The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.本研究报道了第二代快速骨骼肌肌钙蛋白激活剂（fast skeletal muscle troponin activator, FSTA）雷迪塞姆替夫（reldesemtiv）的发现——该药物可在次最大刺激频率下提升肌肉力量生成能力。研究团队通过对高通量筛选得到的1号命中化合物开展基于性质的优化，获得了相较于第一代FSTA替拉塞姆替夫（tirasemtiv）具有更优游离药物暴露水平与体内肌肉激活活性的化合物。雷迪塞姆替夫在I期临床试验中已展现出增强的肌肉力量生成效果，目前正处于针对肌萎缩侧索硬化症（amyotrophic lateral sclerosis）的临床试验评估阶段。