ChemicalBook Product Catalog Biochemical Engineering Inhibitors Transmembrane Transporters ATPase activator OMecaMtiv Mecarbil

OMecaMtiv Mecarbil

Product NameOMecaMtiv Mecarbil
CAS873697-71-3
MFC20H24FN5O3
MW401.43
EINECS850-774-6
MOL File873697-71-3.mol

Chemical Properties

Melting point	180℃
storage temp.	-20°C Freezer
solubility	DMSO (Slightly), Methanol (Slightly)
form	Solid
color	White to Off-White
Water Solubility	40.25mg/L at 25℃
InChI	InChI=1S/C20H24FN5O3/c1-14-6-7-16(12-22-14)23-19(27)24-17-5-3-4-15(18(17)21)13-25-8-10-26(11-9-25)20(28)29-2/h3-7,12H,8-11,13H2,1-2H3,(H2,23,24,27)
InChIKey	RFUBTTPMWSKEIW-UHFFFAOYSA-N
SMILES	N1(C(OC)=O)CCN(CC2=CC=CC(NC(NC3=CC=C(C)N=C3)=O)=C2F)CC1
LogP	-0.531

Usage And Synthesis

Description

Omecamtiv mecarbil (CK-1827452) is a specific cardiac myosin activator and a clinical drug for left ventricular systolic heart failure. Phase 2.

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.

Definition

ChEBI: Omecamtiv mecarbil is a member of ureas.

Biological Activity

omecamtiv mecarbil (ck-1827452) is the first potent cardiac myosin activator that can specifically activate the cardiac myosin s1 domain but not other muscle myosins. in

in vivo

Omecamtiv mecarbil (100-1000 ng/mL) demonstrates concentration-dependent increases in FS in SpragueDawley rats model. Omecamtiv mecarbil demonstrates good PK parameters in both rats (SpragueDawley) and dogs (Beagle) with clearances of 22 and 7.2 mL/min/kg, volumes of 3.5 and 3.6 L/kg, and bioavailabilities (F%) of 100 and 80%, respectively^[1]. Omecamtiv mecarbil does not affect the phosphorylation status of myofilament proteins in both WT and KO hearts as shown by the absence of significant differences between pre and post Omecamtiv mecarbil samples within WT and KO groups, or affect the force generation at maximal Ca²⁺ activation (pCa 4.5) in any of the groups. Omecamtiv mecarbil increases the responsiveness of the cardiac myofilaments to Ca²⁺ at submaximal Ca²⁺-activations^[2].

target

ATPase

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.