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.