GSK269962A-GSK-269962-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGSK269962ACat. No.: HY-15556CAS No.: 850664-21-0Synonyms: GSK 269962分式: CHNO分量: 570.6作靶點: ROCK作通路: Cell Cycle/DNA Damage; Stem Cell/Wnt; TGF-beta/Smad儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實

2、驗 DMSO : 30 mg/mL (52.58 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 1.7525 mL 8.7627 mL 17.5254 mL5 mM 0.3505 mL 1.7525 mL 3.5051 mL10 mM 0.1753 mL 0.8763 mL 1.7525 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 GSK269962A種有效的

3、ROCK 抑制劑，作于重 組 ROCK1 和 ROCK2，IC50 分別為 1.6 和 4 nM。IC50 & Target ROCK1 ROCK2 RSK1 MSK11.6 nM (IC50) 4 nM (IC50) 132 nM (IC50) 49 nM (IC50)1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEAKT1 AKT2 AKT3 CDK2955 nM (IC50) 1350 nM (IC50) 1510 nM (IC50) 3500 nM (IC50)GSK31260 nM (IC50)體外研究 GSK269962A IC50

4、 values of 1.6 nM toward recombinant human ROCK1. GSK269962A also exhibits morethan 30-fold selectivity against a panel of serine/threonine kinases. GSK269962A induces vasorelaxation inpreconstricted rat aorta with an IC50 of 35 nM. Both are highly potent toward human ROCK1 with IC50 of 1.6nM for GS

5、K269962A. On the other hand, GSK269962A has a significantly improved kinase selectivity profilewith at least 30-fold selectivity against the panel of protein kinase tested 1.體內(nèi)研究 Oral administration of GSK269965A (0.3, 1, and 3 mg/kg) induces a dose-dependent reduction in bloodpressure in spontaneou

6、sly hypertensive rat (SHR). The reduction of blood pressure is acute and substantial.The maximal effect on blood pressure is observed approximately 2 h after oral gavages for both compounds.Under a similar setting, oral administration of Y-27632 (10 and 30 mg/kg) also induced a dose-dependentdecreas

7、e of blood pressure. For all three Rho kinase inhibitors, the reduction of blood pressure isaccompanied by an acute, dose-dependent increase in heart rate, presumably due to the activation ofbaroreflex mechanism 1.PROTOCOLKinase Assay 1 The enzyme activity and kinetics of the purified ROCK1(3-543) a

8、re determined using scintillation proximityassay. In this assay, purified ROCK1 is incubated with peptide substrate (Biotin-Ahx-AKRRLSSLRA-CONH2), and 33ATP and the subsequent incorporation of 33P into the peptide is quantified by streptavidinbead capture. For IC50 determination, test compounds are

9、dissolved at 10 mM in 100% DMSO, withsubsequent serial dilution in 100% DMSO. Compounds are typically assayed over an 11-point dilution rangewith a concentration in the assay of 10 M to 0.2 nM in 3-fold dilutions. For dose-response curves, data arenormalized and expressed as percentage inhibition us

10、ing the formula 100(U-C1)/(C2-C1), where U is theunknown value, C1 is the average of the high signal (0%) control wells, and C2 is the average of the lowsignal (100%) control wells. Curve fitting is performed The results for each compound are recorded as pIC50values 1.MCE has not independently confi

11、rmed the accuracy of these methods. They are for reference only.Animal Rats 1Administration 1 Male Sprague-Dawley rats (350-400g) are anesthetized with 5% isoflurane in O2 and killed byexsanguination. Aortic rings, approximately 2 to 3 mm in length, are suspended by two 0.1-mm diametertungsten wire

12、hooks in 10 mL tissue baths containing Krebs of the following composition: 112 mM NaCl, 4.7mM KCl, 2.5 mM CaCl2, 1.2 mM KH2PO2, 1.2 mM MgSO4, 25 mM NaHCO3, 11.0 mM dextrose, 0.01 mMindomethacin, and 0.01 mM L-NAME. Krebs is maintained at 37C and aerated with 95% O2, 5% CO2, pH7.4,. Changes in isomet

13、ric force are measured under optimal resting tension (1 g) using FT03 force-displacement transducers coupled to model 7D polygraphs. After a 60-min equilibration period, the vesselsare treated with standard concentrations of KCl (60 mM) and phenylephrine (1 M). Cumulative2/3 Master of Small Molecule

14、s 您邊的抑制劑師www.MedChemEconcentration-response curves to phenylephrine are obtained for each tissue by dosing at 0.5-log unitintervals (1 nM to 10 M). After several washes, each vessel is contracted to equilibrium with an EC80concentration of phenylephrine, and tone is reversed by adding cumulative amo

15、unts of either GSK269962Aor SB-772077-B at 0.5-log unit intervals (0.1 nM to 1 M). Responses are expressed as percentage reversalof the tone established with phenylephrine.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Doe C, et al. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmac