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H-1152 dihydrochloride

Rho-kinase inhibitor CAS# 871543-07-6

H-1152 dihydrochloride

Catalog No. BCC1616----Order now to get a substantial discount!

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Chemical structure

H-1152 dihydrochloride

3D structure

Chemical Properties of H-1152 dihydrochloride

Cas No. 871543-07-6 SDF Download SDF
PubChem ID 11560225 Appearance Powder
Formula C16H23Cl2N3O2S M.Wt 392.34
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 32 mg/mL (81.56 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-methyl-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline;dihydrochloride
SMILES CC1CNCCCN1S(=O)(=O)C2=CC=CC3=CN=CC(=C32)C.Cl.Cl
Standard InChIKey BFOPDSJOLUQULZ-GXKRWWSZSA-N
Standard InChI InChI=1S/C16H21N3O2S.2ClH/c1-12-9-18-11-14-5-3-6-15(16(12)14)22(20,21)19-8-4-7-17-10-13(19)2;;/h3,5-6,9,11,13,17H,4,7-8,10H2,1-2H3;2*1H/t13-;;/m0../s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of H-1152 dihydrochloride

DescriptionRho-kinase (ROCK) inhibitor that displays high selectivity over other protein kinases (IC50 values are 0.012, 0.180, 0.360, 0.745, 3.03, 5.68 and 28.3 μM for ROCKII, CAMKII, PKG, Aurora A, PKA, PKC and MLCK respectively). Inhibits sulprostone-induced contractions in guinea pig aorta (IC50 = 190 nM) and displays proerectile effects in rats. Glycyl derivative available.

H-1152 dihydrochloride Dilution Calculator

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Preparing Stock Solutions of H-1152 dihydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.5488 mL 12.744 mL 25.4881 mL 50.9762 mL 63.7202 mL
5 mM 0.5098 mL 2.5488 mL 5.0976 mL 10.1952 mL 12.744 mL
10 mM 0.2549 mL 1.2744 mL 2.5488 mL 5.0976 mL 6.372 mL
50 mM 0.051 mL 0.2549 mL 0.5098 mL 1.0195 mL 1.2744 mL
100 mM 0.0255 mL 0.1274 mL 0.2549 mL 0.5098 mL 0.6372 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on H-1152 dihydrochloride

H-1152, an isoquinolinesulfonamide derivative, is a potent, selective and membrane-permeable inhibitor of Rho-kinase with a Ki value of 1.6 nM, revealing a high selectivity over other serine/threonine kinases.
In human neuroteratoma (NT-2) cells, H-1152 has shown to dose-dependently block lysophosphatidic acid (LPA)-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation with an IC50 value of 2.5 μM [1].
Human trabecular meshwork (HTM) cells treated with H-1152 has been revealed cell elongation and separation, deterioration, focal adhesions, and loss of actin stress fibers. Rat eyes treated with H-1152 has been demonstrated a remarkable decrease in intraocular pressure (IOP) and an expansion of the intercellular spaces and loss of extracellular material in the juxtacanalicular region of the TM [2].
H-1152 has been revealed to increase population of neurite lengths in dissociated cultures of postnatal mouse spiral ganglia.However, H1152 has shown to have no effect on reducing alterations in different neuronal morphologies ratios or neuronal survival [3].
H-1152 has shown to lead to rightward shifts in the curves to phenylephrine (PE) with no significant effect on the electrical field stimulation (EFS) induced contractions. In addition, H-1152 at 100 nmol/kg administrated intraperitoneally has been revealed to remarkably increase cavernous nerve stimulation induced erectile responses [4]
References:
1.Ikenoya M1, Hidaka H, Hosoya T, Suzuki M, Yamamoto N, Sasaki Y. Inhibition of rho-kinase-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation in human neuronal cells by H-1152, a novel and specific Rho-kinase inhibitor. J Neurochem. 2002 Apr;81(1):9-16.
2.Yu M1, Chen X, Wang N, Cai S, Li N, Qiu J, Brandt CR, Kaufman PL, Liu X.
H-1152 effects on intraocular pressure and trabecular meshwork morphology of rat eyes. J Ocul Pharmacol Ther. 2008 Aug;24(4):373-9. doi: 10.1089/jop.2008.0029.
3.Lie M1, Grover M, Whitlon DS. Accelerated neurite growth from spiral ganglion neurons exposed to the Rho kinase inhibitor H-1152. Neuroscience. 2010 Aug 25;169(2):855-62. doi: 10.1016/j.neuroscience.2010.05.020. Epub 2010 May 15.
4.Teixeira CE1, Ying Z, Webb RC. Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis. J Pharmacol Exp Ther. 2005 Oct;315(1):155-62. Epub 2005 Jun 23.

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References on H-1152 dihydrochloride

Role of protein kinase Czeta and calcium entry in KCl-induced vascular smooth muscle calcium sensitization and feedback control of cellular calcium levels.[Pubmed:19011165]

J Pharmacol Exp Ther. 2009 Feb;328(2):399-408.

The degree of tonic force (F) maintenance induced in vascular smooth muscle upon K(+) depolarization with 110 mM KCl can be greatly reduced by inhibition of rhoA kinase (ROCK). We explored the possibility that a protein kinase C (PKC) isotype may also play a role in causing KCl-induced Ca(2+) sensitization. In isometric rings of rabbit artery, the PKC inhibitors, Go-6983 (3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyr role-2,5-dione), GF-109203X (2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide), and a cell-permeable (myristoylated) pseudosubstrate inhibitor of PKCzeta (PI(PKCzeta)) inhibited KCl-induced tonic F. A myristoylated pseudosubstrate inhibitor of PKCalpha/beta that inhibited phorbol dibutyrate-induced F slightly potentiated KCl-induced tonic F and attenuated 30 mM KCl-induced F. Although the ROCK inhibitor, H-1152 [(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)-sulfonyl]-hexahydro-1H-1,4-diazep ine dihydrochloride], reduced basal phosphorylation of myosin light-chain phosphatase-targeting subunit at Thr853 (MYPT1-pT853), 3 and 10 muM GF-109203X inhibited only KCl-stimulated phosphorylation, not basal MYPT1-pT853. In fura-2-loaded tissues, GF-109203X and PI(PKCzeta) elevated basal [Ca(2+)](i) (calcium) and potentiated KCl-induced tonic increases in calcium while reducing KCl-induced tonic increases in F. Blockade by nifedipine of Ca(2+) entry through voltage-operated Ca(2+) channels reduced KCl-induced Ca(2+) sensitization and KCl-stimulated but not basal MYPT1-pT853. These data together support a model in which ROCK and PKCzeta are constitutively active and function in "resting" muscle to regulate the basal levels of MYPT1-pT853 and calcium, respectively. In this model, KCl-induced increases in calcium activate PKCzeta to feed forward and cause additional MYPT1-pT853 above that induced by constitutive ROCK, permitting Ca(2+) sensitization and strong F maintenance. Active PKCzeta also feeds back to attenuate the degree of KCl-induced increases in calcium.

Development of specific Rho-kinase inhibitors and their clinical application.[Pubmed:16213195]

Biochim Biophys Acta. 2005 Dec 30;1754(1-2):245-52.

Hexahydro-1-(isoquinoline-5-sulfonyl)-1H-1,4-diazepine, HA-1077, is a known selective inhibitor of Rho-kinase. Although its IC(50) value against Rho-kinase is more than 10 times lower than those for kinases such as PKA, PKB, PKC, PKG, MLCK, CaMKII and others, the molecule still retains relative potent inhibition activities against these kinases. In order to produce highly specific Rho-kinase inhibitors, several HA-1077 analogs were synthesized and their kinase inhibition properties evaluated. (S)-Hexahydro-1-(4-ethenylisoquinoline-5-sulfonyl)-2-methyl-1H-1,4-diazepine was found to be a potent Rho-kinase inhibitor. The IC50 value against Rho-kinase was 6 nM, while those against other kinases remained at almost the same level as that of HA-1077. Furthermore, we designed HA-1077 analogs on the basis of the complex structure of PKA and HA-1077. Amongst these, (S)-hexahydro-4-glycyl-2-methyl-1-(4-methylisoquinoline-5-sulfonyl)-1H-1,4-diazep ine and other glycine derivatives were found to be highly specific Rho-kinase inhibitors. These Rho-kinase specific inhibitors were applied to rabbit ocular hypertensive models and were shown to reduce intraocular pressure. These results demonstrate that the new 5-isoquinolinesulfonylamides are not only potent ROCK selective compounds, but are also useful compounds for clinical applications.

Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis.[Pubmed:15976017]

J Pharmacol Exp Ther. 2005 Oct;315(1):155-62.

The Rho-kinase pathway mediates Ca2+ sensitization in the penile circulation, which maintains the penis in the flaccid state. We aimed to investigate the functional effect of a novel Rho-kinase inhibitor, H-1152 [(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine], both in vitro and in vivo as well as to demonstrate the expression of Rho guanine nucleotide exchange factors (RhoGEFs) in the rat corpus cavernosum (CC), by using a semiquantitative reverse transcription-polymerase chain reaction assay to measure their mRNA expression. Cumulative addition of H-1152 (0.001-3 microM) or Y-27632 [0.01-30 microM; (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] caused sustained relaxations of precontracted CC strips, which were not affected by inhibition of the nitric oxide signaling pathway. Addition of H-1152 (0.1 microM), Y-27632 (1 microM), or sodium nitroprusside (SNP; 0.1 microM) caused rightward shifts in the curves to phenylephrine (PE), but it had little effect on the contractions mediated by electrical field stimulation (EFS). It is noteworthy that when H-1152 or Y-27632 was combined with SNP, a marked synergistic inhibition was noted both on PE- and EFS-induced contractions. Intraperitoneal administration of H-1152 (100 nmol/kg) had a discrete effect on mean arterial pressure and significantly enhanced erectile responses evoked by stimulation of the cavernous nerve. The mRNA expression for PDZ-RhoGEF, p115RhoGEF, and leukemia-associated RhoGEF in cavernosal segments was visualized by electrophoresis on agarose gel. The results indicate that H-1152 is a powerful Rho-kinase inhibitor, giving rise to its therapeutic potential in the treatment of erectile dysfunction. The regulator of G-protein signaling-containing RhoGEFs may represent key components of the molecular mechanisms associated with the abnormal function of the cavernosal smooth muscle.

Involvement of Rho-kinase in contraction of guinea-pig aorta induced by prostanoid EP3 receptor agonists.[Pubmed:12922932]

Br J Pharmacol. 2003 Aug;139(8):1449-61.

1. The mechanism of contraction of guinea-pig isolated aorta induced by the prostanoid EP(3) receptor agonist sulprostone (0.1-300 nM) has been investigated. In 60% of the experiments, the sulprostone log concentration-response curve (maximum=15-40% of 100 nM U-46619 response; low-responders) was unaffected by the removal of extracellular Ca(2+), blockade of L-type Ca(2+) channels with nifedipine and depletion of internal Ca(2+) stores. In the remaining preparations (35-65% of 100 nM U-46619 response; high-responders), contractions to higher sulprostone concentrations showed a nifedipine-sensitive component, which was enhanced by charybdotoxin. 2. In Ca(2+)-free Krebs solution, established contractions to 300 nM sulprostone were abolished by the Rho-kinase inhibitors H-1152, Y-27632 and HA-1077 (IC(50) values=190, 770 and 2030 nM). The PKA/Rho-kinase inhibitor H-89 (10 nM-10 micro M) caused enhancement progressing to inhibition. The selective PKC inhibitor Ro 32-0432 (3 micro M) had no effect, while staurosporine, recently shown to be a potent Rho-kinase inhibitor, abolished sulprostone responses (IC(50) approximately 47 nM), but its action was slow. The MAP kinase inhibitors SB 202190, SB 203580 and PD 80958 produced little inhibition. 3. In normal Krebs solution, H-1152 and Y-27632 abolished established contractions to 300 nM sulprostone and 1 micro M phenylephrine, and partially inhibited 10 micro M phenylephrine and 50 mM K(+) responses. 4. The results are discussed in relation to the reported potencies of the protein kinase inhibitors in enzyme assays. Activation of the Rho-kinase pathway appears to be a primary mechanism of contraction induced by EP(3) receptor agonists in guinea-pig aorta.

Description

H-1152 dihydrochloride is a membrane-permeable and selective ROCK inhibitor, with a Ki value of 1.6 nM, and an IC50 value of 12 nM for ROCK2.

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