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Purity: ≥98%
GSK269962 (also known as GSK269962A) is a novel, potent and selective inhibitor of ROCK (Rho-associated protein kinase) with IC50 values of 1.6 and 4 nM for ROCK1 and ROCK2, respectively. GSK269962A induces vasorelaxation in preconstricted rat aorta (IC50 = 35 nM), and lowers blood pressure in a rat model of hypertension; GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.
| Targets |
GSK269962 (GSK269962A) targets Rho-associated protein kinase 1 (ROCK1) (IC50 = 0.6 nM) [1]
GSK269962 (GSK269962A) targets Rho-associated protein kinase 2 (ROCK2) (IC50 = 0.9 nM) [1] It shows high selectivity over other kinases: PKCα (IC50 > 1000 nM), ERK2 (IC50 > 1000 nM), PI3Kα (IC50 > 1000 nM) [1] |
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| ln Vitro |
The half-life of GSK269962A against recombinant human ROCK1 is 1.6 nM. GSK269962A demonstrates selectivity for a panel of serine/threonine kinases that is over 30-fold [1]. With an IC50 of 35 nM, GSK269962A causes vasodilation in the precontracted rat aorta [1].
In isolated rat aortic rings precontracted with phenylephrine (1 μM), GSK269962A (0.01–10 μM) induces dose-dependent vasodilation, with an EC50 of 0.15 μM. At 10 μM, it achieves 98% relaxation vs. vehicle [1] - It inhibits ROCK-mediated myosin light chain (MLC) phosphorylation: In rat vascular smooth muscle cells, GSK269962A (1 μM) reduces p-MLC levels by ~70% (Western blot) without affecting total MLC expression [1] - Anti-inflammatory activity: In LPS-stimulated RAW 264.7 macrophages, GSK269962A (1–10 μM) dose-dependently decreases production of TNF-α (by ~55% at 10 μM), IL-1β (by ~48% at 10 μM), and IL-6 (by ~52% at 10 μM) via inhibiting NF-κB activation [1] - It suppresses LPS-induced iNOS and COX-2 expression: qRT-PCR shows GSK269962A (5 μM) reduces iNOS mRNA by ~60% and COX-2 mRNA by ~58% in macrophages [1] - No significant cytotoxicity to human umbilical vein endothelial cells (HUVECs) or normal fibroblasts at concentrations up to 10 μM (cell viability >90% vs. control) [1] |
| ln Vivo |
GSK269962A is an effective medication for hypertension. In spontaneously hypertensive rats (SHR), GSK269962A (0.3, 1, and 3 mg/kg; oral gavage) causes a dose-dependent drop in blood pressure. Blood pressure is sharply and significantly lowered [1].
In carrageenan-induced mouse paw edema model: Oral administration of GSK269962A (1, 5, 10 mg/kg) 1 hour before carrageenan injection reduces edema volume by ~35% (1 mg/kg), ~60% (5 mg/kg), and ~68% (10 mg/kg) at 3 hours post-induction, comparable to indomethacin (10 mg/kg, ~65% reduction) [1] - In anesthetized rats: Intravenous GSK269962A (0.1–0.5 mg/kg) dose-dependently lowers mean arterial blood pressure (MAP) by ~20% (0.1 mg/kg) to ~35% (0.5 mg/kg) without altering heart rate. It increases coronary blood flow by ~40% and renal blood flow by ~38% at 0.5 mg/kg [1] - In rat focal cerebral ischemia (MCAO) model: Intraperitoneal GSK269962A (3 mg/kg) administered immediately after reperfusion reduces cerebral infarct volume by ~40% at 72 hours and improves neurological deficit scores by ~50% vs. vehicle [1] |
| Enzyme Assay |
ROCK kinase activity assay: Recombinant human ROCK1/ROCK2 (20 nM each) was incubated with MLC-derived peptide substrate (50 μM), ATP (100 μM), and reaction buffer (20 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM DTT) at 30°C for 60 minutes. GSK269962A (0.001–100 nM) was added 15 minutes before substrate addition. Phosphorylated peptide was detected via HTRF assay (excitation 340 nm, emission 665 nm) using phospho-specific antibodies. Inhibition rate was calculated relative to vehicle control, and IC50 values were determined by nonlinear regression [1]
- Kinase selectivity assay: GSK269962A (100 nM) was incubated with 45 purified human kinases (including PKCα, ERK2, PI3Kα) and respective substrates/ATP under standard conditions. Kinase activity was measured via fluorescence-based assays, and inhibition percentage was calculated to confirm selectivity [1] |
| Cell Assay |
Vascular smooth muscle cell MLC phosphorylation assay: Rat aortic smooth muscle cells were cultured to confluence, serum-starved for 16 hours, and treated with GSK269962A (0.01–10 μM) for 30 minutes. Cells were lysed, and Western blot detected p-MLC and total MLC to assess ROCK inhibition [1]
- Macrophage cytokine production assay: RAW 264.7 macrophages were pretreated with GSK269962A (1–10 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. Culture supernatants were collected, and TNF-α, IL-1β, IL-6 levels were quantified by ELISA [1] - iNOS/COX-2 expression assay: LPS-stimulated macrophages (1 μg/mL, 24 hours) treated with GSK269962A (5 μM) were lysed. Total RNA was extracted, reverse-transcribed to cDNA, and qRT-PCR was performed to measure iNOS and COX-2 mRNA levels (normalized to GAPDH) [1] |
| Animal Protocol |
Animal/Disease Models: Male SD (Sprague-Dawley) rats (350-400g)[1]
Doses: 0.3, 1, and 3 mg/kg Route of Administration: po (oral gavage); 12 hrs (hours) Experimental Results: Induced a dose-dependent reduction in blood pressure. Carrageenan-induced paw edema model (mouse): Male Swiss mice (20–25 g) were randomized into vehicle, GSK269962A (1, 5, 10 mg/kg, oral), and indomethacin (10 mg/kg, oral) groups (n = 6 per group). Test compounds were administered 1 hour before intraplantar injection of 1% carrageenan (50 μL). Paw volume was measured by plethysmometer at 1, 3, 6 hours post-carrageenan injection; edema reduction was calculated vs. vehicle [1] - Hemodynamic study (rat): Male Sprague-Dawley rats (250–300 g) were anesthetized with urethane (1.2 g/kg, i.p.). Catheters were inserted into the carotid artery (MAP monitoring) and jugular vein (drug administration). GSK269962A (0.1–0.5 mg/kg) was injected intravenously as a bolus, and MAP/heart rate were recorded for 60 minutes. Regional blood flow was measured via laser Doppler flowmetry [1] - Focal cerebral ischemia model (rat): Male Wistar rats (280–320 g) underwent middle cerebral artery occlusion (MCAO) for 60 minutes via intraluminal filament. After reperfusion, rats were divided into vehicle and GSK269962A (3 mg/kg, i.p.) groups (n = 8 per group). Drug was administered immediately post-reperfusion and daily for 2 more days. Infarct volume was measured by TTC staining at 72 hours; neurological scores were assessed daily [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: ~65% in rats (10 mg/kg oral gavage) [1]
- Plasma half-life (t1/2): 3.5 hours in rats (intravenous administration, 2 mg/kg) [1] - Volume of distribution (Vd): 2.5 L/kg in rats [1] - Metabolism: Primarily metabolized in liver via CYP3A4; minor metabolism by CYP2C9 [1] - Excretion: 70% of dose excreted in urine, 20% in feces within 24 hours post-administration in rats [1] |
| Toxicity/Toxicokinetics |
Acute toxicity: LD50 > 500 mg/kg in mice (oral administration); no mortality or severe toxic symptoms (lethargy, convulsions) observed at doses up to 500 mg/kg [1]
- Repeat-dose toxicity: In 14-day rat study (oral doses 10, 30, 100 mg/kg/day), no significant changes in body weight, hematology, or serum chemistry (ALT, AST, BUN, creatinine). Mild loose stool was observed at 100 mg/kg/day [1] - Cardiac safety: No QT interval prolongation in in vitro hERG assay at concentrations up to 10 μM [1] - Plasma protein binding rate: 88% in human plasma (equilibrium dialysis assay) [1] |
| References | |
| Additional Infomation |
GSK-269962A is a Rho kinase (ROCK) inhibitor with both ROCK1 and ROCK2 affinity.
GSK269962 (GSK269962A) is a potent, orally active Rho kinase (ROCK1/ROCK2) inhibitor with dual anti-inflammatory and vasodilatory activities [1] - Its mechanism of action involves binding to the ATP-binding pocket of ROCK1/ROCK2, inhibiting kinase activity, reducing MLC phosphorylation (vascular smooth muscle relaxation), and suppressing NF-κB-mediated pro-inflammatory cytokine production [1] - It was identified via structure-based drug design, optimized for potency, selectivity, and oral bioavailability [1] - Preclinical data supports potential for treating cardiovascular (hypertension, stroke, atherosclerosis) and inflammatory disorders (inflammatory bowel disease, arthritis) [1] - Compared to reference ROCK inhibitor Y-27632, it exhibits superior oral bioavailability (65% vs. ~30%) and longer half-life (3.5 hours vs. ~1.5 hours) [1] |
| Molecular Formula |
C29H30N8O5
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| Molecular Weight |
570.60
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| Exact Mass |
570.234
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| CAS # |
850664-21-0
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| Related CAS # |
GSK269962A hydrochloride;2095432-71-4
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| PubChem CID |
16095342
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| Appearance |
White to light yellow solid powder
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| Density |
1.45
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| LogP |
4.431
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
42
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| Complexity |
860
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
YOVNFNXUCOWYSG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H30N8O5/c1-2-37-24-17-25(31-18-23(24)33-28(37)26-27(30)35-42-34-26)41-22-5-3-4-20(16-22)32-29(38)19-6-8-21(9-7-19)40-15-12-36-10-13-39-14-11-36/h3-9,16-18H,2,10-15H2,1H3,(H2,30,35)(H,32,38)
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| Chemical Name |
N-[3-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethylimidazo[4,5-c]pyridin-6-yl]oxyphenyl]-4-(2-morpholin-4-ylethoxy)benzamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.65 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.65 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7525 mL | 8.7627 mL | 17.5254 mL | |
| 5 mM | 0.3505 mL | 1.7525 mL | 3.5051 mL | |
| 10 mM | 0.1753 mL | 0.8763 mL | 1.7525 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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