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.
ABSTRACT
Compounds with similar target specificities and modes of inhibition cause similar cellular phenotypes. Based on this observation, we hypothesized that we could quantitatively classify compounds with diverse mechanisms of action using cellular phenotypes and identify compounds with unintended cellular activities within a chemical series. We have developed Cytometrix technologies, a highly automated image-based system capable of quantifying, clustering, and classifying changes in cellular phenotypes for this purpose. Using this system, 45 out of 51 known compounds were accurately classified into 12 distinct mechanisms of action. We also demonstrate microtubule-binding activity in one of seven related cytochalasin actin poisons. This technology can be used for a variety of drug discovery applications, including high-throughput primary screening of chemical and siRNA libraries and as a secondary assay to detect unintended activities and toxicities.