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(Synonyms: CK-2127107) 目录号 : GC61239

Reldesemtiv(CK-2127107)是一种选择性的,口服活性的下一代快速骨骼肌肌钙蛋白(fastskeletalmuscletroponin)激活剂(FSTA)。Reldesemtiv选择性激活快速骨骼肌原纤维,EC50为3.4μM。Reldesemtiv可提高心力衰竭模型的运动表现。

Reldesemtiv Chemical Structure

Cas No.:1345410-31-2

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5mg
¥4,320.00
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10mg
¥7,200.00
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25mg
¥13,950.00
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50mg
¥22,500.00
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100mg
¥34,200.00
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产品描述

Reldesemtiv (CK-2127107) is a selective, orally active and next-generation fast skeletal muscle troponin activator (FSTA). Reldesemtiv selectively activates fast skeletal myofibrils with an EC50 of 3.4 μM. Reldesemtiv increases exercise performance in a heart failure model[1].

Reldesemtiv selectively binds to and sensitizes the fast skeletal troponin complex to calcium[1].

Reldesemtiv (10 mg/kg; p.o.) significantly improves rotarod performance in exercise-intolerant LAD-HF rats[1].Reldesemtiv (10 mg/kg; i.v.) increases Ca2+ sensitivity in fast skeletal muscle fibers and increases muscle force in response to submaximal stimulation frequencies in LAD-HF rats[1].Reldesemtiv increases sarcomeric Ca2+ sensitivity in skinned LAD-HF skeletal fibers[1]. Animal Model: Female Sprague-Dawley rats (Sham and left anterior descending coronary artery (LAD) heart failure (LAD-HF))[1]

[1]. Hwee DT, et al. The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure. J Pharmacol Exp Ther. 2015 Apr;353(1):159-68. [2]. Andrews JA, et al. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. 2018 May;57(5):729-734.

Chemical Properties

Cas No. 1345410-31-2 SDF
别名 CK-2127107
Canonical SMILES O=C(C1=CN(C2=CN=C(NC[C@]3(C4=NC=CC=C4F)C[C@H](F)C3)N=C2)C=C1)N
分子式 C19H18F2N6O 分子量 384.38
溶解度 DMSO : 250 mg/mL (650.40 mM; Need ultrasonic) 储存条件 Store at -20°C
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 2.6016 mL 13.008 mL 26.0159 mL
5 mM 0.5203 mL 2.6016 mL 5.2032 mL
10 mM 0.2602 mL 1.3008 mL 2.6016 mL
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Research Update

Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study

Neurotherapeutics 2021 Apr;18(2):1127-1136.PMID:33624184DOI:10.1007/s13311-020-01004-3.

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral Reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending Reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of Reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to Reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for Reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on Reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest Reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of Reldesemtiv were well tolerated. Results suggest Reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS

Amyotroph Lateral Scler Frontotemporal Degener 2021 May;22(3-4):287-299.PMID:32969758DOI:10.1080/21678421.2020.1822410.

To evaluate safety, dose response, and preliminary efficacy of Reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to Reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring Reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of Reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

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

J Med Chem 2021 Oct 28;64(20):14930-14941.PMID:34636234DOI:10.1021/acs.jmedchem.1c01067.

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.

Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of Reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial

Amyotroph Lateral Scler Frontotemporal Degener 2022 May;23(3-4):263-270.PMID:34218726DOI:10.1080/21678421.2021.1946083.

Objective: To evaluate the possible effect of Reldesemtiv, a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Methods: Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each Reldesemtiv dose with placebo. Post hoc analyses evaluated all Reldesemtiv doses compared with placebo. Results: At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving Reldesemtiv 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving Reldesemtiv 150 mg bid vs placebo (17.0% vs 28.9%, p = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all Reldesemtiv doses combined was 0.61 (confidence interval: 0.39, 0.96, p = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for reldesemtiv-treated patients at 120 days. Conclusions: Results suggest ALS patients receiving Reldesemtiv may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression.

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

Front Pharmacol 2022 Nov 28;13:1054006.PMID:36518658DOI:10.3389/fphar.2022.1054006.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. In the recent past, there have been just two drugs approved for treatment, riluzole and edaravone, which only prolong survival by a few months. However, there are many novel experimental drugs in development. In this review, we summarize 53 new drugs that have been evaluated in clinical trials from 2020 to 2022, which we have classified into eight mechanistic groups (anti-apoptotic, anti-inflammatory, anti-excitotoxicity, regulated integrated stress response, neurotrophic factors and neuroprotection, anti-aggregation, gene therapy and other). Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and Reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone.