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

Abstract

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 20 Pg. 14930-14941 (10 28 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34636234 (Publication Type: Journal Article)

Chemical References

• Troponin

Topics

• Dose-Response Relationship, Drug
• Drug Discovery
• Humans
• Molecular Structure
• Muscle, Skeletal (drug effects, metabolism, pathology)
• Structure-Activity Relationship
• Troponin (metabolism)