CK-1827452, a sarcomere-directed cardiac myosin activator for acute and chronic heart disease.
Cytokinetics Inc is developing CK-1827452, an agent that directly activates myosin, for use in the treatment of heart failure. The reaction of myosin cross-bridges from the thick myofilaments of cardiac sarcomeres with actin molecules from the thin myofilaments induces the muscle force and shortening that is responsible for systolic pressure development and ejection. Preclinical in vitro studies with isolated proteins investigated the mode of action of CK-1827452, demonstrating the ability of the drug to prolong the duration of time that myosin motors remain in a force-generating reaction with actin. Studies with isolated field-stimulated cardiac myocytes demonstrated the critical property of enhancing the extent of myocyte shortening, with no effect on the Ca2+ transient. Thus, CK-1827452 represents a novel myosin activator that acts independently of Ca2+, with an advantage compared with inotropic agents that elevate cAMP, enhance Ca2+ fluxes and have the potential to induce arrhythmias. Phase II clinical trials in patients with heart failure treated with intravenous and/or oral formulations of CK-1827452 support the hypothesis that the direct activation of myosin is a well-tolerated and viable approach to improving cardiac function. CK-1827452 represents a new and promising class of pure sarcomeric activators with a novel mechanism that could be an improvement over existing agents acting in part through this mechanism.
Solaro
R John
RJ
University of Illinois at Chicago, College of Medicine, Department of Physiology and Biophysics M/C 901, 835 South Wolcott Avenue, Chicago, IL 60612, USA. solarorj@uic.edu
D000208:Acute Disease; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002908:Chronic Disease; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D012518:Sarcomeres / Q000187:drug effects* / Q000378:metabolism; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D009218:Myosins