Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator.
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ABSTRACT:
SUBMITTER: Collibee SE
PROVIDER: S-EPMC5900333 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
Publications
Discovery of <i>Tirasemtiv</i>, the First Direct Fast Skeletal Muscle Troponin Activator.
Collibee Scott E SE Bergnes Gustave G Muci Alexander A Browne William F WF Garard Marc M Hinken Aaron C AC Russell Alan J AJ Suehiro Ion I Hartman James J Kawas Raja R Lu Pu-Ping PP Lee Kenneth H KH Marquez David D Tomlinson Matthew M Xu Donghong D Kennedy Adam A Hwee Darren D Schaletzky Julia J Leung Kwan K Malik Fady I FI Morgans David J DJ Morgan Bradley P BP
ACS medicinal chemistry letters 20180213 4
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 scleros ...[more]
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Project description:Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1 G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1 G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.
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2020-11-30 | GSE160827 | GEO