RESUMEN
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.