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

Collibee, Scott E.; Bergnes, Gustave; Chuang, Chihyuan; Ashcraft, Luke; Gardina, Jeffrey; Garard, Marc; Jamison, Chris R.; Lu, Kevin; Lu, Pu-Ping; Muci, Alexander; Romero, Antonio; Valkevich, Ellen; Wang, Wenyue; Warrington, Jeffrey; Yao, Bing; Durham, Nickie; Hartman, James; Marquez, Anna; Hinken, Aaron; Schaletzky, Julia; Xu, Donghong; Hwee, Darren T.; Morgans, David; Malik, Fady I.; Morgan, Bradley P.

doi:10.1021/acs.jmedchem.1c01067.s001

jm1c01067_si_001.pdf (1.29 MB)

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

journal contribution

posted on 2021-10-12, 12:07 authored by Scott E. Collibee, Gustave Bergnes, Chihyuan Chuang, Luke Ashcraft, Jeffrey Gardina, Marc Garard, Chris R. Jamison, Kevin Lu, Pu-Ping Lu, Alexander Muci, Antonio Romero, Ellen Valkevich, Wenyue Wang, Jeffrey Warrington, Bing Yao, Nickie Durham, James Hartman, Anna Marquez, Aaron Hinken, Julia Schaletzky, Donghong Xu, Darren T. Hwee, David Morgans, Fady I. Malik, Bradley P. Morgan

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.