Vesnarinone - CAS 81840-15-5
Catalog number: 81840-15-5
Category: Inhibitor
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Molecular Formula:
C22H25N3O4
Molecular Weight:
395.45
COA:
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Targets:
Phosphodiesterase (PDE)
Description:
Vesnarinone, a quinolinone derivative, is a cardiotonic agent. It has pharmacodynamic effects include inhibition of phosphodiesterase III (PDE3) activity, increases in calcium flux and decreases in potassium flux. Its IC50 value is 1 μM and 300 μM for inhibition of HERG channels and PDE. It is a novel cytokine inhibitor, for the treatment of lung fibrosis using a murine model of bleomycin (BLM)-induced pulmonary fibrosis. It is a new and novel inotropic drug that has unique and complex mechanisms of action. It inhibits phosphodiesterase, thereby leading to increased intracellular calcium, and also affects numerous myocardial ion channels, resulting in the prolongation of the opening time of sodium channels and the decrease in the delayed outward and inward rectifying potassium current. It plays an important role in the regulation of cytokines and suggests that the reduction of cytokine release may contribute to the beneficial effects of the drug in the treatment of heart failure. It inhibits the production of TFN-a and IFN-y by LPS stimulated whole blood from patients with heart failure and from healthy volunteers. It reduces the circulating levels of TNF-α in vivo. It improves ventricular performance most in patients with the worst degree of heart failure.
Purity:
>98%
Appearance:
Solid powder
Synonyms:
RG-0210; RG 0210; RG0210; OPC-8212; OPC 8212; OPC8212; Piteranometozine; Vesnarinone; Arkin; Arkin-Z. OPC 8212;6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone;3,4-Dihydro-6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-2(1h)-quinolinone
Solubility:
10 mM in DMSO
Storage:
-20°C Freezer
MSDS:
Inquire
Application:
Vesnarinone inhibits phosphodiesterase, thereby leading to increased intracellular calcium, and also affects numerous myocardial ion channels, resulting in the prolongation of the opening time of sodium channels and the decrease in the delayed outward and inward rectifying potassium current. It improves ventricular performance most in patients with the worst degree of heart failure.
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
Quantity:
Milligrams-Grams
Boiling Point:
678.3±55.0 °C | Condition: Press: 760 Torr
Melting Point:
238.1-239.8 °C
Density:
1.246±0.06 g/cm3 | Condition: Temp: 20 °C Press: 760 Torr
InChIKey:
ZVNYJIZDIRKMBF-UHFFFAOYSA-N
InChI:
InChI=1S/C22H25N3O4/c1-28-19-7-3-16(14-20(19)29-2)22(27)25-11-9-24(10-12-25)17-5-6-18-15(13-17)4-8-21(26)23-18/h3,5-7,13-14H,4,8-12H2,1-2H3,(H,23,26)
Canonical SMILES:
COC1=C(C=C(C=C1)C(=O)N2CCN(CC2)C3=CC4=C(C=C3)NC(=O)CC4)OC
Current Developer:
Vesnarinone has been listed.
1.In silico risk assessment for drug-induction of cardiac arrhythmia.
Suzuki S1, Murakami S, Tsujimae K, Findlay I, Kurachi Y. Prog Biophys Mol Biol. 2008 Sep;98(1):52-60. doi: 10.1016/j.pbiomolbio.2008.05.003. Epub 2008 May 29.
The main components of repolarization reserve for the ventricular action potential (AP) are the rapid (I(Kr)) and slow (I(Ks)) delayed outward K(+) currents. While many drugs block I(Kr) and cause life-threatening arrhythmias including torsades de pointes, the frequency of arrhythmias varies between different I(Kr)-blockers. Different types of block of I(Kr) cause distinct phenotypes of prolongation of action potential duration (APD), increase in transmural dispersion of repolarization (TDR) and, accordingly, occurrence of torsades de pointes. Therefore the assessment of a drug's proarrhythmic risk requires a method that provides quantitative and comprehensive comparison of the effects of different forms of I(Kr)-blockade upon APDs and TDR. However, most currently available methods are not adapted to such an extensive comparison. Here, we introduce I(Kr)-I(Ks) two-dimensional maps of APD and TDR as a novel risk-assessment method. Taking the kinetics of I(Kr)-blockade into account, APDs can be calculated upon a ventricular AP model which systematically alters the magnitudes of I(Kr) and I(Ks).
2.The progress towards the development of DHQO derivatives and related analogues with inotropic effects.
Wu Y1, Piao HR. Mini Rev Med Chem. 2013 Oct;13(12):1801-11.
During the course of the past two decades, our group has worked towards the development of increasingly potent inotropic agents by making structural modifications to compounds derived from 3,4-dihydro-2(1H)-quinolinone (DHQO) and related analogues. Herein, we describe the design and synthesis of a new series of DHQO derivatives and the subsequent evaluation of their positive inotropic activity towards left atrium stroke volume in isolated rabbit-heart preparations. Some of these derivatives presented favorable in vitro activities compared with the reference drug, milrinone, and compound 10a, in particular is currently being investigated as a preclinical drug candidate. This review also describes our progress towards the development of DHQO derivatives and related analogues with positive inotropic activities from 1999 to 2013.
3.Vesnarinone represses the fibrotic changes in murine lung injury induced by bleomycin.
Inage M1, Nakamura H, Saito H, Abe S, Hino T, Takabatake N, Terashita K, Ogura M, Kato S, Hosokawa T, Sata M, Tomoike H. Int J Biol Sci. 2009;5(4):304-10. Epub 2009 Apr 16.
We investigated the potential usefulness of vesnarinone, a novel cytokine inhibitor, for the treatment of lung fibrosis using a murine model of bleomycin (BLM)-induced pulmonary fibrosis. Mice were fed a control diet (n=42), or a diet containing low (n=42) or high (n=42) dose of vesnarinone. Dietary intake of vesnarinone minimized the BLM toxicity as reflected by significant decreases in numbers of inflammatory cells, KC, and soluble TNF receptors in the bronchoalveolar lavage fluid. A quantitative evaluation of histology demonstrated significantly mild lung parenchymal lesions in BLM-treated mice fed with diet containing high dose of vesnarinone than in the control diet group. Consistent with the histopathology, hydroxyproline levels in lung tissue from BLM-treated mice fed with diet containing vesnarinone were significantly lower than that from mice fed with control diet. We concluded that vesnarinone inhibits BLM-induced pulmonary fibrosis, at least in part, by the inhibition of acute lung injuries in the early phase.
4.Vesnarinone suppresses TNFα mRNA expression by inhibiting valosin-containing protein.
Hotta K1, Nashimoto A, Yasumura E, Suzuki M, Azuma M, Iizumi Y, Shima D, Nabeshima R, Hiramoto M, Okada A, Sakata-Sogawa K, Tokunaga M, Ito T, Ando H, Sakamoto S, Kabe Y, Aizawa S, Imai T, Yamaguchi Y, Watanabe H, Handa H. Mol Pharmacol. 2013 May;83(5):930-8. doi: 10.1124/mol.112.081935. Epub 2013 Feb 7.
Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IκBα to activate nuclear factor (NF)κB. We show that vesnarinone impairs the degradation of IκBα, and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression.
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CAS 81840-15-5 Vesnarinone

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