Discovery of<i>Tirasemtiv</i>, the First Direct Fast Skeletal Muscle Troponin Activator

Abstract

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound <b>1</b> was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of <b>1</b> for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (<b>25</b>), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.