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

Collibee, Scott E.; Bergnes, Gustave; Chuang, Chih-Yuan; Ashcraft, Luke; J, Gardina; Garard, Marc; Jamison, Chris R.; Lu, Pu-Ping; Muci, Alexander R.; Romero, Antonio; Valkevich, Ellen; Wang, Wenyue; Warrington, Jeffrey M.; Yao, Bing; Durham, Nickie; Hartman, James J.; Marquez, Anna; Hinken, Aaron C.; Schaletzky, Julia; Xu, Donghong; Hwee, Darren T.; Morgans, David J.; Malik, Fady I.; Morgan, Bradley

doi:10.1021/acs.jmedchem.1c01067

Cited by 19 publications

(17 citation statements)

References 27 publications

(36 reference statements)

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“…This difluoromethyl analogue was smoothly furnished in 60% yield. Lastly, 2w , prepared in 69% yield from Tirasemtiv, contains an imidazo[4,5- b ]pyrazinone scaffold commonly encountered in small molecules that target muscle weakness caused by neurogenic diseases. , Throughout the exploration of the substrate scope, we encountered two limitations of the method. Compounds with scaffolds like F1 or F2 were not able to undergo difluoromethylation under these conditions (Scheme i) and instead, 1,1,2,2-tetrafluoroethane { 19 F NMR (CDCl 3 ) δ −139 (d, 55 Hz)} was formed as the major product (see the Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes

et al. 2023

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An efficient method for the direct C(sp)–H difluoromethylation of terminal alkynes and the desilylation–difluoromethylation of (trimethylsilyl)acetylenes is disclosed. The copper-catalyzed transformation provides access to a wide range of structurally diverse CF2H alkynes in good yields, utilizing a (difluoromethyl)zinc reagent and an organic oxidant. The difluoromethylation of important synthons and API’s is showcased. The synthetic utility of these (difluoromethyl)alkynes is demonstrated by selected cycloaddition reactions. Additionally, a slight modification to the reaction conditions allowed the selective preparation of a 2-difluoromethylindole.

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Section: Resultsmentioning

confidence: 99%

Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes

et al. 2023

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“…It selectively binds the troponin complex, slows the release of calcium from troponin C, and sensitizes the sarcomere to calcium. This makes the force-calcium relationship of muscle fibers and force-frequency relationship of a nerve-muscle pair shift leftwards, increasing the muscle’s response to neural input and enhancing strength at submaximal stimulation frequencies ( Collibee et al, 2021 ; Shefner et al, 2021 ). The restoration of skeletal muscle function may preserve the integrity of NMJs and slowing the impairment of motor neurons ( Lepore et al, 2019 ).…”

Section: Drugsmentioning

confidence: 99%

“…Reldesemtiv is more potent than the first-generation fast skeletal muscle troponin activator tirasemtiv, which shares the same mechanism ( Li et al, 2021 ), as it does not cross the blood‒brain barrier, is associated with milder adverse events, and the doses are lower ( Collibee et al, 2021 ). The results from a phase 2 study showed that Reldesemtiv was well tolerated.…”

Section: Drugsmentioning

confidence: 99%

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

2022

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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.

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“…Cardiac sarcomere activators continue to be explored as potential new treatments in heart failure with reduced ejection fraction (HFrEF). 1,2 An area of continued unmet medical need for heart failure patients is in conditions where the contractility of the right ventricle is reduced. For example, congenital heart disease (CHD) is characterized by a range of cardiac birth defects that affect the normal function of the heart.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility

Romero,

Ashcraft,

Chandra

et al. 2024

J. Med. Chem.

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Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug–drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

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

Cited by 19 publications

References 27 publications

Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes

Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes

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

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility

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