SB-747651A Dihydrochloride is an inhibitor of mitogen- and stress-activated kinase 1 (MSK1), a nuclear kinase that phosphorylates histone H3 at serine 10 (H3S10). It is used to block the terminal step in the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway [2].

In rat hippocampus neurons that have been grown, GYKI 52466 (0.3-100 μM) blocks inward currents that are triggered by AMPA and the Kainate receptor[1].

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In human SW872 liposarcoma cells, SB-747651A Dihydrochloride (10 μM) blocks the ability of risperidone to reverse lipopolysaccharide (LPS)-induced heterochromatin formation. When added concurrently with risperidone for the final 24 h of a 48-h LPS treatment, SB-747651A prevents the risperidone-mediated increase in phospho-H3S10 and decrease in H3K9me2 at the IL-6, TNF-α, and IL-1β promoters. Under these conditions, chromatin modifications remain at levels indistinguishable from LPS-only treatment (i.e., elevated H3K9me2 and reduced phospho-H3S10), indicating that MSK1 inhibition abrogates the chromatin-remodeling effects of risperidone [2].

Neutrophil adhesion is enhanced by SB747651A (3 mg/kg; intrascrotal injection) dihydrochloride 3.5~4.5 hours after CXCL2 stimulation in comparison to CXCL2's effect[3]. In a mouse peritonitis model of acute inflammation, SB-747651A (3 mg/kg; ip) dihydrochloride influences neutrophil extravasation by enhancing neutrophil emigration only at 3 and 4 hours[3].

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In mouse cremaster muscle, superfusion with SB-747651A Dihydrochloride (5 μM) for 30 min prior to and 60 min following CXCL2 stimulation significantly increases leukocyte rolling flux (83.7 ± 3.4 vs. 48.3 ± 3.1 cells/min) and rolling velocity (64.4 ± 2.8 vs. 46.9 ± 5.8 μm/s) compared to CXCL2 alone [1].

SB-747651A (5 μM superfusion) enhances CXCL2-induced neutrophil adhesion but reduces emigration at early time points (30–60 min) [1].

Intrascrotal injection of SB-747651A (3 mg/kg, 1 h prior to CXCL2) increases neutrophil adhesion and emigration at 3.5–4.5 h after CXCL2 stimulation [1].

SB-747651A (5 μM superfusion) reduces intraluminal crawling velocity of neutrophils (from 25.2 ± 2.8 to 15.8 ± 1.8 μm/min) and increases both transmigration time (from 2.4 ± 0.2 to 3.3 ± 0.2 min) and detachment time (from 2.5 ± 0.2 to 3.5 ± 0.2 min) in response to CXCL2 [1].

SB-747651A (5 μM superfusion) reduces the migration speed of neutrophils in cremasteric tissue (from 11.0 ± 0.7 to 7.8 ± 0.5 μm/min) but does not affect chemotaxis index [1].

In a mouse peritonitis model, intraperitoneal SB-747651A (3 mg/kg, 30 min prior to CXCL2) does not affect neutrophil emigration at 1–2 h but significantly increases emigrated neutrophils at 3 and 4 h after CXCL2 injection [1].

Human SW872 liposarcoma cells were cultured in RPMI-1640 medium with 10% FBS and penicillin/streptomycin. Cells at approximately 75% confluency were treated with LPS (100 ng/mL) for 48 h to establish heterochromatin. For the final 24 h of the 48-h LPS treatment, cells were co-treated with risperidone (10 μM) alone or with risperidone plus SB-747651A Dihydrochloride (10 μM). Chromatin immunoprecipitation (ChIP) was performed using antibodies against H3K9me2 and phospho-H3S10. Quantitative real-time PCR was conducted using primers specific for the promoters of IL-6, TNF-α, IL-1β, and the negative control KLF-4. Results showed that SB-747651A blocked the risperidone-induced reduction of H3K9me2 and the risperidone-induced increase of phospho-H3S10 at the target gene promoters [2].

Animal/Disease Models: Male C57BL/6N mice (8~16 weeks)[3]
Doses: 3 mg/kg
Route of Administration: Intrascrotal injection
Experimental Results: Resulted in increased neutrophil adhesion 3.5~4.5 hrs (hours) following stimulation with CXCL2 as compared to the effect of CXCL2.

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Male C57BL/6N mice (8–16 weeks old) were used. For intravital microscopy of the cremaster muscle, mice were anesthetized with xylazine (10 mg/kg) and ketamine (200 mg/kg) intraperitoneally. The cremaster muscle was superfused with bicarbonate-buffered saline at 37°C. To study early neutrophil recruitment, a 1-mm³ agarose gel containing CXCL2 (0.5 μM) was placed on the cremaster muscle, and SB-747651A (5 μM) was superfused for 30 min prior to and 60 min following gel placement. For later time points, CXCL2 (0.2 μg in 100 μL saline) was injected intrascrotally, and SB-747651A (3 mg/kg) was administered intrascrotally 1 h prior to CXCL2. Neutrophil recruitment parameters were recorded via bright-field intravital microscopy and analyzed offline [1].

For peritonitis experiments, mice received intraperitoneal injection of CXCL2 (0.5 μg/mouse). SB-747651A (3 mg/kg) was administered intraperitoneally 30 min prior to CXCL2. Peritoneal lavage was collected at 1, 2, 3, 4, and 6 h post-CXCL2, and emigrated neutrophils were counted [1].

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Male C57BL/6N mice (8–16 weeks old) were used. For intravital microscopy of the cremaster muscle, mice were anesthetized with xylazine (10 mg/kg) and ketamine (200 mg/kg) intraperitoneally. The cremaster muscle was superfused with bicarbonate-buffered saline at 37°C. To study early neutrophil recruitment, a 1-mm³ agarose gel containing CXCL2 (0.5 μM) was placed on the cremaster muscle, and SB-747651A (5 μM) was superfused for 30 min prior to and 60 min following gel placement. For later time points, CXCL2 (0.2 μg in 100 μL saline) was injected intrascrotally, and SB-747651A (3 mg/kg) was administered intrascrotally 1 h prior to CXCL2. Neutrophil recruitment parameters were recorded via bright-field intravital microscopy and analyzed offline [1].

For peritonitis experiments, mice received intraperitoneal injection of CXCL2 (0.5 μg/mouse). SB-747651A (3 mg/kg) was administered intraperitoneally 30 min prior to CXCL2. Peritoneal lavage was collected at 1, 2, 3, 4, and 6 h post-CXCL2, and emigrated neutrophils were counted [1].

[1]. Characterization of the cellular action of the MSK inhibitor SB-747651A. Biochem J. 2012 Jan 1;441(1):347-57.

[2]. Risperidone effects on heterochromatin: the role of kinase signaling. Clin Exp Immunol. 2019;196(1):67-75.

[3]. The Specific Mitogen- and Stress-Activated Protein Kinase MSK1 Inhibitor SB-747651A Modulates Chemokine-Induced Neutrophil Recruitment. Int J Mol Sci. 2017;18(10):2163. Published 2017 Oct 17.

SB-747651A Dihydrochloride is a selective inhibitor of MSK1, a downstream kinase in the AC/PKA signaling pathway that directly phosphorylates histone H3 at serine 10 (H3S10). In this study, it was used as a pharmacological tool to demonstrate that the chromatin-remodeling effects of risperidone—specifically the reversal of LPS-induced heterochromatin—are mediated through the AC/PKA/MSK1 signaling cascade. The inhibition of MSK1 by SB-747651A abrogated the ability of risperidone to normalize heterochromatin marks at proinflammatory gene promoters, supporting the role of this kinase pathway in the epigenetic effects of antipsychotic drugs [2].

C16H24CL2N8O

415.32

414.145

1781882-72-1

SB-747651A;607372-46-3

90488958

White to off-white solid powder

5

8

5

27

434

0

C(N1C(C2=NON=C2N)=NC2=CN=CC(CNC3CCNCC3)=C12)C.Cl

NRRCQHARLPNLHJ-UHFFFAOYSA-N

InChI=1S/C16H22N8O.2ClH/c1-2-24-14-10(8-20-11-3-5-18-6-4-11)7-19-9-12(14)21-16(24)13-15(17)23-25-22-13;;/h7,9,11,18,20H,2-6,8H2,1H3,(H2,17,23);2*1H

4-[1-ethyl-7-[(piperidin-4-ylamino)methyl]imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine;dihydrochloride

SB747651A dihydrochloride SB-747651A dihydrochloride SB 747651A dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~50 mg/mL (~120.39 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)