Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0177)
Name
Levosimendan
Synonyms
LEVOSIMENDAN; 141505-33-1; Simdax; (R)-Simendan; Levosimedan; (-)-OR-1259; OR-1259; Simendan, (r)-; CHEBI:50567; NSC-759644; 2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile; DTXSID9046445; C6T4514L4E; OR1259; (R)-((4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono) propanedintrile; (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide; Levosimendan [INN]; Mesoxalonitrile (p-((R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-pyridazinyl)phenyl)hydrazone; DTXCID7026445; levosimendanum; ((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile; Simsndan;OR-1259; 1-cyano-N-{4-[(4R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}methanecarbohydrazonoyl cyanide; SMR002529692; Simdax (TN); CAS-141505-33-1; Levosimendan (USAN/INN); Levosimendan [USAN:INN]; OR 1259; UNII-C6T4514L4E; Levosimendan- Bio-X; LEVOSIMENDAN [MI]; LEVOSIMENDAN [USAN]; Mesoxalonitrile (-)-(p((R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazone; SCHEMBL83243; LEVOSIMENDAN [MART.]; MLS003899227; MLS006010741; LEVOSIMENDAN [WHO-DD]; CHEMBL2051955; Levosimendan, >=98% (HPLC); WHXMKTBCFHIYNQ-SECBINFHSA-N; HMS3264G03; HMS3884N17; KUC109648N; Pharmakon1600-01502356; BCP07048; Tox21_112191; Tox21_113768; BDBM50469700; MFCD00867135; NSC759644; s2446; AKOS015895214; Tox21_112191_1; AC-1752; AM84381; CCG-213048; DB00922; DS-8918; NSC 759644; ({4-[(4R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}hydrazono)propanedintrile; 2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazono]propanedinitrile; KSC-210-010; NCGC00253641-01; NCGC00263564-01; NCGC00263564-02; BM164625; HY-14286; L0320; SW219172-1; A11874; D04720; N12889; AB01562970_01; AB01562970_02; A807767; EN300-18567987; Q162541; SR-01000931342; SR-01000931342-2; 1-beta-D-Ribofuranose-1H-1,2,4-triazole-3-methylcarbonate; (R)-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide; (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyldicyanide; 2-(2-(4-((4R)-1,4,5,6-TETRAHYDRO-4-METHYL-6-OXO-3-PYRIDAZINYL)PHENYL)HYDRAZINYLIDENE)PROPANEDINITRILE; Mesoxalonitrile (-)-(p((R)-1,4,5,6-tetrahydro-4-methyl-6- oxo-3-pyridazinyl)phenyl)hydrazone; PROPANEDINITRILE, ((4-(1,4,5,6-TETRAHYDRO-4-METHYL-6-OXO-3-PYRIDAZINYL)PHENYL)HYDRAZONO)-, (R)-; PROPANEDINITRILE, 2-(2-(4-((4R)-1,4,5,6-TETRAHYDRO-4-METHYL-6-OXO-3-PYRIDAZINYL)PHENYL)HYDRAZINYLIDENE)-

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Status
Approved
Drug Type
Small molecular drug
Structure
Formula
C14H12N6O
IUPAC Name
2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile
Canonical SMILES
CC1CC(=O)NN=C1C2=CC=C(C=C2)NN=C(C#N)C#N
InChI
InChI=1S/C14H12N6O/c1-9-6-13(21)19-20-14(9)10-2-4-11(5-3-10)17-18-12(7-15)8-16/h2-5,9,17H,6H2,1H3,(H,19,21)/t9-/m1/s1
InChIKey
WHXMKTBCFHIYNQ-SECBINFHSA-N
PubChem CID
3033825
TTD Drug ID
D0C4HG
Full List of Ferroptosis Target Related to This Drug
Unspecific Target
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Responsed Disease Left ventricular failure ICD-11: BD11
 Disease Info 
Responsed Regulator Gap junction alpha-1 protein (GJA1) Suppressor
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model rHTs (Rat hippocampal tissues)
In Vivo Model
We purchased forty-eight 3-week-old male C57BL/6N mice from Beijing HFK Bioscience Co. Ltd. and gave a twelve-hour light and dark cycle starting from 06:00 (am) to 18:00 (pm). Mice were randomly assigned into three groups after 2 weeks of adaptive feeding as follows. (1) The control group (n = 16): mice were provided with normal drinking water, a normal diet and intraperitoneal administration of solvent (5% DMSO + 40% Peg300 + 5% Tween 80 + 50% ddH2O) 3 mL/kg once a week aged 13 to 17 weeks. (2) The HFpEF group (n = 16): a double-hit model was designed, in which metabolic and mechanical stress worked together and resulted in HFpEF. Briefly, C57BL/6N mice had unrestricted access to a high-fat diet (HFD, D12492, Research Diet) starting from 5 weeks old. Meanwhile, a nitric oxide synthase inhibitor, N (gamma)-nitro-L-arginine methyl ester (L-NAME) (N5751, Sigma) was supplied in drinking water (0.5 g/L) for HFpEF groups, and the pH of the drinking water was adjusted to 7.4. The above placebo solvent was administrated in the same manner. (3) The HFpEF + Levo group (n = 16): according to the previous study, HFpEF mice received 3 mg/kg levosimendan (S2446, Selleck) (Dissolve 1 mg of levosimendan in 50 uL of DMSO, subsequently dilute to 1 mg/mL with the above solvent) intraperitoneally once a week from week 13 to 17.

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Response regulation Levosimendan reversed mitochondrial malfunction in HFpEF mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels. Levosimendan Reverses Cardiac Malfunction and Cardiomyocyte Ferroptosis During Heart Failure with Preserved Ejection Fraction via Connexin 43 Signaling Activation.
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Left ventricular failure ICD-11: BD11
 Disease Info 
Pathway Response Glutathione metabolism hsa00480
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model rHTs (Rat hippocampal tissues)
In Vivo Model
We purchased forty-eight 3-week-old male C57BL/6N mice from Beijing HFK Bioscience Co. Ltd. and gave a twelve-hour light and dark cycle starting from 06:00 (am) to 18:00 (pm). Mice were randomly assigned into three groups after 2 weeks of adaptive feeding as follows. (1) The control group (n = 16): mice were provided with normal drinking water, a normal diet and intraperitoneal administration of solvent (5% DMSO + 40% Peg300 + 5% Tween 80 + 50% ddH2O) 3 mL/kg once a week aged 13 to 17 weeks. (2) The HFpEF group (n = 16): a double-hit model was designed, in which metabolic and mechanical stress worked together and resulted in HFpEF. Briefly, C57BL/6N mice had unrestricted access to a high-fat diet (HFD, D12492, Research Diet) starting from 5 weeks old. Meanwhile, a nitric oxide synthase inhibitor, N (gamma)-nitro-L-arginine methyl ester (L-NAME) (N5751, Sigma) was supplied in drinking water (0.5 g/L) for HFpEF groups, and the pH of the drinking water was adjusted to 7.4. The above placebo solvent was administrated in the same manner. (3) The HFpEF + Levo group (n = 16): according to the previous study, HFpEF mice received 3 mg/kg levosimendan (S2446, Selleck) (Dissolve 1 mg of levosimendan in 50 uL of DMSO, subsequently dilute to 1 mg/mL with the above solvent) intraperitoneally once a week from week 13 to 17.

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Response regulation Levosimendan reversed mitochondrial malfunction in heart failure with preserved ejection fraction (HFpEF) mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels. Levosimendan reverses cardiac malfunction and cardiomyocyte ferroptosis during heart failure with preserved ejection fraction via connexin 43 signaling activation.
NADPH oxidase 4 (NOX4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Driver
Responsed Disease Left ventricular failure ICD-11: BD11
 Disease Info 
Pathway Response Glutathione metabolism hsa00480
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model rHTs (Rat hippocampal tissues)
In Vivo Model
We purchased forty-eight 3-week-old male C57BL/6N mice from Beijing HFK Bioscience Co. Ltd. and gave a twelve-hour light and dark cycle starting from 06:00 (am) to 18:00 (pm). Mice were randomly assigned into three groups after 2 weeks of adaptive feeding as follows. (1) The control group (n = 16): mice were provided with normal drinking water, a normal diet and intraperitoneal administration of solvent (5% DMSO + 40% Peg300 + 5% Tween 80 + 50% ddH2O) 3 mL/kg once a week aged 13 to 17 weeks. (2) The HFpEF group (n = 16): a double-hit model was designed, in which metabolic and mechanical stress worked together and resulted in HFpEF. Briefly, C57BL/6N mice had unrestricted access to a high-fat diet (HFD, D12492, Research Diet) starting from 5 weeks old. Meanwhile, a nitric oxide synthase inhibitor, N (gamma)-nitro-L-arginine methyl ester (L-NAME) (N5751, Sigma) was supplied in drinking water (0.5 g/L) for HFpEF groups, and the pH of the drinking water was adjusted to 7.4. The above placebo solvent was administrated in the same manner. (3) The HFpEF + Levo group (n = 16): according to the previous study, HFpEF mice received 3 mg/kg levosimendan (S2446, Selleck) (Dissolve 1 mg of levosimendan in 50 uL of DMSO, subsequently dilute to 1 mg/mL with the above solvent) intraperitoneally once a week from week 13 to 17.

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Response regulation Levosimendan reversed mitochondrial malfunction in heart failure with preserved ejection fraction (HFpEF) mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels. Levosimendan reverses cardiac malfunction and cardiomyocyte ferroptosis during heart failure with preserved ejection fraction via connexin 43 signaling activation.
Ferroptosis suppressor protein 1 (AIFM2)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Left ventricular failure ICD-11: BD11
 Disease Info 
Pathway Response Glutathione metabolism hsa00480
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model rHTs (Rat hippocampal tissues)
In Vivo Model
We purchased forty-eight 3-week-old male C57BL/6N mice from Beijing HFK Bioscience Co. Ltd. and gave a twelve-hour light and dark cycle starting from 06:00 (am) to 18:00 (pm). Mice were randomly assigned into three groups after 2 weeks of adaptive feeding as follows. (1) The control group (n = 16): mice were provided with normal drinking water, a normal diet and intraperitoneal administration of solvent (5% DMSO + 40% Peg300 + 5% Tween 80 + 50% ddH2O) 3 mL/kg once a week aged 13 to 17 weeks. (2) The HFpEF group (n = 16): a double-hit model was designed, in which metabolic and mechanical stress worked together and resulted in HFpEF. Briefly, C57BL/6N mice had unrestricted access to a high-fat diet (HFD, D12492, Research Diet) starting from 5 weeks old. Meanwhile, a nitric oxide synthase inhibitor, N (gamma)-nitro-L-arginine methyl ester (L-NAME) (N5751, Sigma) was supplied in drinking water (0.5 g/L) for HFpEF groups, and the pH of the drinking water was adjusted to 7.4. The above placebo solvent was administrated in the same manner. (3) The HFpEF + Levo group (n = 16): according to the previous study, HFpEF mice received 3 mg/kg levosimendan (S2446, Selleck) (Dissolve 1 mg of levosimendan in 50 uL of DMSO, subsequently dilute to 1 mg/mL with the above solvent) intraperitoneally once a week from week 13 to 17.

    Click to Show/Hide
Response regulation Levosimendan reversed mitochondrial malfunction in heart failure with preserved ejection fraction (HFpEF) mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels. Levosimendan reverses cardiac malfunction and cardiomyocyte ferroptosis during heart failure with preserved ejection fraction via connexin 43 signaling activation.
References
Ref 1 Levosimendan Reverses Cardiac Malfunction and Cardiomyocyte Ferroptosis During Heart Failure with Preserved Ejection Fraction via Connexin 43 Signaling Activation. Cardiovasc Drugs Ther. 2023 Mar 7. doi: 10.1007/s10557-023-07441-4. Online ahead of print.