ABSTRACT
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.
Subject(s)
Cardiac Myosins/metabolism , Heart Failure, Systolic/drug therapy , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Urea/analogs & derivatives , Actin Cytoskeleton/metabolism , Actins/metabolism , Adenosine Triphosphatases/metabolism , Adenosine Triphosphate/metabolism , Adrenergic beta-Agonists/pharmacology , Allosteric Regulation , Animals , Binding Sites , Calcium/metabolism , Cardiac Myosins/chemistry , Cardiac Output/drug effects , Dogs , Female , Heart Failure, Systolic/physiopathology , Isoproterenol/pharmacology , Male , Myocytes, Cardiac/physiology , Phosphates/metabolism , Protein Binding , Protein Conformation , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Rats , Rats, Sprague-Dawley , Urea/chemistry , Urea/metabolism , Urea/pharmacology , Ventricular Function, Left/drug effectsABSTRACT
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.