In vitro
In vitro, Omecamtiv mecarbil selectively activates cardiac myosin by increasing the myosin ATPase rate. In isolated cardiac myocytes, Omecamtiv mecarbil results in increase of myocyte contractility and overcomes of the myosin inhibitor BDM without increasing the calcium transient or inhibiting the PDE pathway. [
In vivo
Omecamtiv mecarbil significantly increases fractional shortening starting at 0.4 mM plasma concentrations in SD rats, sham animals and in rats with heart failure. In conscious dogs with myocardial infarction (MI-sHF), Omecamtiv mecarbil leads to a significant increase in wall thickening (25%), stroke volume (44%), cardiac output (22%) and left ventricular (LV) systolic ejection time (26%). In addition, Omecamtiv mecarbil also results in the decreases of some hemodynamic parameters including heart rate, mean left atrial pressure, and LV end-diastolic pressure. In conscious dogs with left ventricular hypertrophy (LVH-sHF), Omecamtiv mecarbil leads to similar and not statistically different effects on hemodynamic parameters.
Uses
CK 1827452 is a promising new drug in systolic heart failure. It accelerates the transition of myosin into the force-generating state without affecting cardiac myocyte calcium homeostasis. CK 1827452 increases cardiac function by increasing the duration of ejection without changing the rates of contraction.
References
1. malik fi1, hartman jj, elias ka, morgan bp, rodriguez h, brejc k, anderson rl, sueoka sh, lee kh, finer jt, sakowicz r, baliga r, cox dr, garard m,godinez g, kawas r, kraynack e, lenzi d, lu pp, muci a, niu c, qian x, pierce dw, pokrovskii m, suehiro i, sylvester s, tochimoto t, valdez c, wang w,katori t, kass da, shen yt, vatner sf, morgans dj. cardiac myosin activation: a potential therapeutic approach for systolic heart failure. science. 2011 mar 18;331(6023):1439-43.
