Inotropic agents are important drug for the treatment of advanced heart failure with low cardiac output. However, the traditional inotropic agents such as catecholamines and PDE3 inhibitors enhance the contractility through enhancing intracellular calcium transient at the cost of increased risk of ischemia, arrhythmia, and cardiac sudden death. To make a novel type of direct sarcomere modulators, which can enhance cardiac contractility independent on the calcium transient, we have been focusing on the phosphorylation of myosin regulatory light chain (RLC). RLC wraps around the alpha helical neck region of myosin heavy chain, and once phosphorylated, the force and speed of cardiac muscle contraction are potentiated without affecting the intracellular calcium transient. We are now developing a new type of direct sarcomere activator that can enhance the phosphorylation level of RLC in cardiac myocytes.