Tirasemtiv

Tirasemtiv, also known as CK2017357, is a novel skeletal muscle activator. Tirasemtiv slows the rate of calcium release from troponin, thus sensitizing fast skeletal muscle fibers to calcium. Tirasemtiv demonstrated increases in skeletal muscle force in response to neuronal input and delays in the onset and reductions in the degree of muscle fatigue. (In Vitro) :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. Tirasemtiv selectively sensitizes fast skeletal muscle troponin to calcium (Ca2+), and slows the rate of Ca2+ release from the regulatory troponin complex of fast skeletal muscle. (In Vivo) :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-SOD1G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in Tirasemtiv-treated female B6SJL-SOD1G93A mice. At the 25% deficit milestone, vehicle-treated B6SJL-SOD1G93A mice demonstrated forelimb grip strength of 49.6±4.6 g. Tirasemtiv increases grip strength by 38% to 68.6±8.1g (p<0.05, single tailed t-test) . Tirasemtiv doses of 2, 2, 2, and 4 mg/kg given at approximately 20 min intervals to achieve a cumulative dose of 10 mg/kg. Regression analysis of the log dose vs. response relationship indicated that Tirasemtiv significantly increased muscle force in WT and mid-stage B6SJL-SOD1G93A mice (WT p<0.0001; mid-stage p=0.0028) . At later stages of disease, the mice exhibited a trend for increased muscle function in response to Tirasemtivcompared to baseline (p=0.064) .