RESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Músculo Esquelético/efectos de los fármacos , Troponina/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Relación Estructura-ActividadRESUMEN
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.
RESUMEN
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.
Asunto(s)
Calcio/metabolismo , Músculo Esquelético/metabolismo , Enfermedades Neuromusculares/metabolismo , Troponina C/agonistas , Troponina C/metabolismo , Adenosina Trifosfatasas/metabolismo , Animales , Bovinos , Humanos , Imidazoles/química , Imidazoles/uso terapéutico , Terapia Molecular Dirigida , Contracción Muscular/efectos de los fármacos , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patología , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/metabolismo , Miastenia Gravis/patología , Miosinas/aislamiento & purificación , Miosinas/metabolismo , Enfermedades Neuromusculares/tratamiento farmacológico , Enfermedades Neuromusculares/patología , Pirazinas/química , Pirazinas/uso terapéutico , Conejos , Ratas , Troponina/metabolismo , Troponina/fisiologíaRESUMEN
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.
Asunto(s)
Miosinas Cardíacas/metabolismo , Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Urea/análogos & derivados , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfato/metabolismo , Agonistas Adrenérgicos beta/farmacología , Regulación Alostérica , Animales , Sitios de Unión , Calcio/metabolismo , Miosinas Cardíacas/química , Gasto Cardíaco/efectos de los fármacos , Perros , Femenino , Insuficiencia Cardíaca Sistólica/fisiopatología , Isoproterenol/farmacología , Masculino , Miocitos Cardíacos/fisiología , Fosfatos/metabolismo , Unión Proteica , Conformación Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Urea/química , Urea/metabolismo , Urea/farmacología , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
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.