CK-1827452

CK-1827452 is a cardiac specific myosin activator. It is clinically tested for its role in the treatment of left ventricular systolic heart failure. CK-1827452 specifically targets and activates myocardial ATPase and improves energy utilization. CK-1827452 improves systolic function by increasing the systolic ejection duration/stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.

Product information

CAS Number: 873697-71-3

Molecular Weight: 401.43

Formula: C20H24FN5O3

Synonym:

Omecamtiv mecarbil

CK 1827452

CK1827452

Chemical Name: methyl4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate

Smiles: CC1=CC=C(C=N1)NC(=O)NC1=CC=CC(CN2CCN(CC2)C(=O)OC)=C1F

InChiKey: RFUBTTPMWSKEIW-UHFFFAOYSA-N

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)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

CK-1827452 (10 μM) reduces the maximal ATPase (kcat) 4.5-fold and dramatically reduces the actin concentration at which ATPase is half-maximal (KATPase) 30-fold. The CK-1827452-induced inhibition of the actin-activated ATPase is evaluated in a concentration-dependent manner to determine the EC50 (0.52 ± 0.10 μM). CK-1827452 does not change the overall actin affinity. CK-1827452 traps a population of myosin heads in a weak actin affinity state with slow product release. CK-1827452 can reduce the actin sliding velocity more than 100-fold in the in vitro motility assay.

In Vivo:

CK-1827452 (100-1000 ng/mL) demonstrates concentration-dependent increases in FS in Sprague−Dawley rats model. CK-1827452 demonstrates good PK parameters in both rats (Sprague−Dawley) 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. CK-1827452 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 CK-1827452 samples within WT and KO groups, or affect the force generation at maximal Ca2+ activation (pCa 4.5) in any of the groups. CK-1827452 increases the responsiveness of the cardiac myofilaments to Ca2+ at submaximal Ca2+-activations.

References:

1. Spinarova L, Spinar J. Pharmacotherapy of dilated cardiomyopathy. Curr Pharm Des. 2014;21(4):449-58. PubMed PMID: 25483945.
2. Greenberg BH, Chou W, Saikali KG, Escandón R, Lee JH, Chen MM, Treshkur T, Megreladze I, Wasserman SM, Eisenberg P, Malik FI, Wolff AA, Shaburishvili T. Safety and Tolerability of Omecamtiv Mecarbil During Exercise in Patients With Ischemic Cardiomyopathy and Angina. JACC Heart Fail. 2014 Nov 11. pii: S2213-1779(14)00379-5. doi: 10.1016/j.jchf.2014.07.009. [Epub ahead of print] PubMed PMID: 25453536.
3. McNeice AH, McAleavey NM, Menown IB. Advances in clinical cardiology. Adv Ther. 2014 Aug;31(8):837-60. doi: 10.1007/s12325-014-0141-9. Epub 2014 Jul 30. PubMed PMID: 25074280.
4. Wang Y, Ajtai K, Burghardt TP. Analytical comparison of natural and pharmaceutical ventricular myosin activators. Biochemistry. 2014 Aug 19;53(32):5298-306. doi: 10.1021/bi500730t. Epub 2014 Aug 7. PubMed PMID: 25068717; PubMed Central PMCID: PMC4139156.
5. Tarone G, Balligand JL, Bauersachs J, Clerk A, De Windt L, Heymans S, Hilfiker-Kleiner D, Hirsch E, Iaccarino G, Knöll R, Leite-Moreira AF, Lourenço AP, Mayr M, Thum T, Tocchetti CG. Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. Eur J Heart Fail. 2014 May;16(5):494-508. doi: 10.1002/ejhf.62. Epub 2014 Mar 17. PubMed PMID: 24639064.

Products are for research use only. Not for human use.