Tirasemtiv
(Synonyms: CK-2017357) 目录号 : GC37799
An activator of the fast skeletal troponin complex
Cas No.:1005491-05-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Mice[1] Wild-type background strain B6SJLF1/J mice and B6SJL-SOD1G93A mice over-expressing the human SOD-1 gene with mutation G93A are group-housed in a 12-hour light cycle and fed standard chow and water ad libitum. Tirasemtiv is administered in solution (50% PEG300/10% EtOH/40% Cavitron cyclodextrin formulation) as a single slow bolus over a 2 minute period via a catheter in the contralateral femoral artery placed above the aortic bifurcation. Tirasemtiv bolus injections (2, 2, 2, and 4 mg/kg) are given at approximately 20 min intervals to achieve a cumulative dose of 10 mg/kg in order to assess the dose response, with a maximal dosage volume of 5 mL/kg. At the end of each experiment, a single terminal blood sample is drawn via cardiac puncture for compound concentration analysis. |
References: [1]. Hwee DT, et al. Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. PLoS One. 2014 May 7;9(5):e96921. | |
Tirasemtiv is an activator of the fast skeletal troponin complex.1 It selectively binds to purified fast skeletal troponin complex (Kd = 40 nM) over slow skeletal (Kd = 3,800 nM) and cardiac troponin complexes. Tirasemtiv (20 μM) slows the rate of calcium release from the fast skeletal troponin complex. It increases the ATPase activity of isolated rabbit fast skeletal myofibrils at a fixed calcium concentration (EC50 = 390 nM) and sensitizes skinned fast skeletal muscle fibers isolated from human and rabbit to calcium in a concentration-dependent manner. Tirasemtiv increases in situ extensor digitorum longus (EDL) muscle force and forelimb grip strength in a rat model of myasthenia gravis. It also increases forelimb grip strength, grid hang test performance, and rotarod performance in a mouse model of amyotrophic lateral sclerosis (ALS) when administered at a dose of 10 mg/kg.2
1.Russell, A.J., Hartman, J.J., Hinken, A.C., et al.Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseasesNat Med.18(3)452-455(2012) 2.Hwee, D.T., Kennedy, A., Ryans, J., et al.Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse modelPLoS One9(5)e96921(2014)
| Cas No. | 1005491-05-3 | SDF | |
| 别名 | CK-2017357 | ||
| Canonical SMILES | O=C1N(C(CC)CC)C2=NC(C#C)=CN=C2N1 | ||
| 分子式 | C12H14N4O | 分子量 | 230.27 |
| 溶解度 | DMSO: ≥ 52 mg/mL (225.82 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.3427 mL | 21.7136 mL | 43.4273 mL |
| 5 mM | 0.8685 mL | 4.3427 mL | 8.6855 mL |
| 10 mM | 0.4343 mL | 2.1714 mL | 4.3427 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle
J Med Chem 2021 Mar 25;64(6):3026-3034.PMID:33703886DOI:10.1021/acs.jmedchem.0c01412.
Troponin regulates the calcium-mediated activation of skeletal muscle. Muscle weakness in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy occurs from diminished neuromuscular output. The first direct fast skeletal troponin activator, Tirasemtiv, amplifies the response of muscle to neuromuscular input. Tirasemtiv binds selectively and strongly to fast skeletal troponin, slowing the rate of calcium release and sensitizing muscle to calcium. We report the solution NMR structure of Tirasemtiv bound to a fast skeletal troponin C-troponin I chimera. The structure reveals that Tirasemtiv binds in a hydrophobic pocket between the regulatory domain of troponin C and the switch region of troponin I, which overlaps with that of Anapoe in the X-ray structure of skeletal troponin. Multiple interactions stabilize the troponin C-troponin I interface, increase the affinity of troponin C for the switch region of fast skeletal troponin I, and drive the equilibrium toward the active state.
Tirasemtiv amplifies skeletal muscle response to nerve activation in humans
Muscle Nerve 2014 Dec;50(6):925-31.PMID:24634285DOI:10.1002/mus.24239.
Introduction: In this study we tested the hypothesis that Tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. Methods: Healthy men received Tirasemtiv and placebo in a randomized, double-blind, 4-period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force-frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. Results: Tirasemtiv increased force produced by the tibialis anterior in a dose-, concentration-, and frequency-dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz). Conclusions: The data confirm that Tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of Tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input.
A phase III trial of Tirasemtiv as a potential treatment for amyotrophic lateral sclerosis
Amyotroph Lateral Scler Frontotemporal Degener 2019;0(0):1-11.PMID:31081694DOI:10.1080/21678421.2019.1612922.
Objective: To assess the efficacy of Tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label Tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target Tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label Tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to Tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the Tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated Tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on Tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of Tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898).
Acute and chronic Tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice
Hum Mol Genet 2021 Jun 26;30(14):1305-1320.PMID:33909041DOI:10.1093/hmg/ddab112.
Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of Tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force-both in vivo and in vitro-in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. In Acta1H40Y mice, treatment with Tirasemtiv increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of Tirasemtiv were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, Tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.
Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator
ACS Med Chem Lett 2018 Feb 13;9(4):354-358.PMID:29670700DOI:10.1021/acsmedchemlett.7b00546.
The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of Tirasemtiv (25), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.