Omecamtiv mecarbil at 10 μM reduces the maximum rate of ATP hydrolysis (kcat) by 4.5-fold and lowers the actin concentration needed for half-maximal ATPase activity (KATPase) by 30-fold. The EC50 of Omecamtiv mecarbil-induced inhibition of actin-activated ATPase is determined to be 0.52 ± 0.10 μM. It does not alter overall actin affinity but causes a state of weak actin affinity in a subset of myosin heads with slow product release. In an in vitro motility assay, it reduces the actin sliding velocity by more than 100-fold[3].
体内研究
Omecamtiv mecarbil, at concentrations between 100-1000 ng/mL, shows dose-dependent increases in fractional shortening (FS) in a Sprague Dawley rat model. Pharmacokinetic parameters in rats and Beagle dogs are favorable, with clearances of 22 mL/min/kg and 7.2 mL/min/kg, volumes of 3.5 L/kg and 3.6 L/kg, and bioavailabilities of 100% and 80%, respectively[1].
Omecamtiv mecarbil does not alter the phosphorylation status of myofilament proteins in either WT or KO hearts, nor does it affect force generation at maximum Ca2+ activation (pCa 4.5) in any group. However, it does increase the responsiveness of cardiac myofilaments to Ca2+ at submaximal activations[2].
体外研究
Omecamtiv mecarbil at 10 μM reduces the maximum rate of ATP hydrolysis (kcat) by 4.5-fold and lowers the actin concentration needed for half-maximal ATPase activity (KATPase) by 30-fold. The EC50 of Omecamtiv mecarbil-induced inhibition of actin-activated ATPase is determined to be 0.52 ± 0.10 μM. It does not alter overall actin affinity but causes a state of weak actin affinity in a subset of myosin heads with slow product release. In an in vitro motility assay, it reduces the actin sliding velocity by more than 100-fold[3].
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