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1.
J Med Chem ; 67(10): 7859-7869, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38451215

RESUMO

Novel cardiac troponin activators were identified using a high throughput cardiac myofibril ATPase assay and confirmed using a series of biochemical and biophysical assays. HTS hit 2 increased rat cardiomyocyte fractional shortening without increasing intracellular calcium concentrations, and the biological target of 1 and 2 was determined to be the cardiac thin filament. Subsequent optimization to increase solubility and remove PDE-3 inhibition led to the discovery of CK-963 and enabled pharmacological evaluation of cardiac troponin activation without the competing effects of PDE-3 inhibition. Rat echocardiography studies using CK-963 demonstrated concentration-dependent increases in cardiac fractional shortening up to 95%. Isothermal calorimetry studies confirmed a direct interaction between CK-963 and a cardiac troponin chimera with a dissociation constant of 11.5 ± 3.2 µM. These results provide evidence that direct activation of cardiac troponin without the confounding effects of PDE-3 inhibition may provide benefit for patients with cardiovascular conditions where contractility is reduced.


Assuntos
Contração Miocárdica , Troponina , Animais , Masculino , Ratos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Troponina/metabolismo
2.
J Med Chem ; 64(20): 14930-14941, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34636234

RESUMO

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.


Assuntos
Descoberta de Drogas , Músculo Esquelético/efeitos dos fármacos , Troponina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Relação Estrutura-Atividade
3.
ACS Med Chem Lett ; 9(4): 354-358, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29670700

RESUMO

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.

4.
Nat Med ; 18(3): 452-5, 2012 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-22344294

RESUMO

Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.


Assuntos
Cálcio/metabolismo , Músculo Esquelético/metabolismo , Doenças Neuromusculares/metabolismo , Troponina C/agonistas , Troponina C/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Bovinos , Humanos , Imidazóis/química , Imidazóis/uso terapêutico , Terapia de Alvo Molecular , Contração Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patologia , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/metabolismo , Miastenia Gravis/patologia , Miosinas/isolamento & purificação , Miosinas/metabolismo , Doenças Neuromusculares/tratamento farmacológico , Doenças Neuromusculares/patologia , Pirazinas/química , Pirazinas/uso terapêutico , Coelhos , Ratos , Troponina/metabolismo , Troponina/fisiologia
5.
Science ; 331(6023): 1439-43, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21415352

RESUMO

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.


Assuntos
Miosinas Cardíacas/metabolismo , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Ureia/análogos & derivados , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Regulação Alostérica , Animais , Sítios de Ligação , Cálcio/metabolismo , Miosinas Cardíacas/química , Débito Cardíaco/efeitos dos fármacos , Cães , Feminino , Insuficiência Cardíaca Sistólica/fisiopatologia , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/fisiologia , Fosfatos/metabolismo , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Ureia/química , Ureia/metabolismo , Ureia/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos
6.
ACS Med Chem Lett ; 1(9): 472-7, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900233

RESUMO

We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.

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