Skepinone-L | CAS#1221485-83-1

Skepinone-L
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WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 530909

CAS#: 1221485-83-1

Description: Skepinone-L is an ATP-competitive inhibitor of p38 MAPK isoform p38α (IC50s = 5 nM) and p38β (97% inhibition at 1 µM).

Chemical Structure

Skepinone-L

CAS# 1221485-83-1

Instruction

Theoretical Analysis

MedKoo Cat#: 530909
Name: Skepinone-L
CAS#: 1221485-83-1
Chemical Formula: C24H21F2NO4
Exact Mass: 425.14
Molecular Weight: 425.430
Elemental Analysis: C, 67.76; H, 4.98; F, 8.93; N, 3.29; O, 15.04

Price and Availability

Size	Price	Availability
5mg	USD 300	2 Weeks
10mg	USD 550	2 Weeks
Bulk inquiry Welcome, Customer: Please do not inquire quote if your intended use is for a patient since our products are for research use and for chemical synthesis use, not for human use . For in-stock products, we listed price in the web page. You may inquire prices for which sizes were not listed. If no price is listed, this means the product is not in stock at the moment, which may be available via custom synthesis. For cost-effective reason, minimum order of 1g is requested (typically very expensive). The lead time is usually 2-4 months. Quote of less than 1g will not be provided. MedKoo may not offer quote for below reasons: (1) current available synthetic method appears to be extremely expensive which is obviously not affordable to most customers; (2) Key raw material to make the product is temporally not available; (3) DEA controlled substances; (4) the product is under patent protection in customer’s country.

Synonym: Skepinone-L,

IUPAC/Chemical Name: 2-[(2,4-difluorophenyl)amino]-7-[(2R)-2,3-dihydroxypropoxy]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one

InChi Key: HXMGCTFLLWPVFM-GOSISDBHSA-N

InChi Code: InChI=1S/C24H21F2NO4/c25-16-4-8-23(22(26)10-16)27-17-5-7-20-15(9-17)2-1-14-3-6-19(11-21(14)24(20)30)31-13-18(29)12-28/h3-11,18,27-29H,1-2,12-13H2/t18-/m1/s1

SMILES Code: O=C1C2=CC=C(NC3=CC=C(F)C=C3F)C=C2CCC4=CC=C(OC[C@H](O)CO)C=C14

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Instruction:

View handling instruction

Biological target:	Skepinone-L is an ATP-competitive inhibitor of p38 MAPK isoform p38α (IC50s = 5 nM) and p38β (97% inhibition at 1 µM). It has little effect on a range of other kinases, including p38γ and p38δ. Skepinone-L dose-dependently blocks the phosphorylation of heat shock protein 27 (HSP27) in response to stimulation with anisomycin in HeLa cells (IC50 = 25 nM) or TNF-α in THP-1 cells.
In vitro activity:	Skepinone-L might provide a promising therapeutic tool to prevent inflammatory cascades in atherosclerosis. In the human leukemia cell line THP-1 and/or primary monocyte-derived macrophages, skepinone-L inhibited eLDL-induced activation of the p38 MAPK pathway, inhibited eLDL induced expression of both CD36 and ABCA1, without a net effect on foam cell formation, had a cell- and time-dependent effect on eLDL-triggered apoptosis, and inhibited eLDL-stimulated secretion of IL-8 and MIP-1β/CCL4. Reference: FASEB J. 2017 Feb;31(2):674-686. https://pubmed.ncbi.nlm.nih.gov/27871059/
In vivo activity:	Intrathecal injection of skepinone prevented formalin induced inflammatory pain in male but not female mice. Intrathecal skepinone reduced chronic constriction injury (CCI) induced neuropathic pain (mechanical allodynia) in male mice on CCI-day 7 but not CCI-day 21. This male-dependent inhibition of neuropathic pain also occurred in rats following intrathecal skepinone. Notably, intraperitoneal or local perineural administration of skepinone inhibited CCI-induced mechanical allodynia in both sexes of mice. Reference: Brain Behav Immun. 2016 Jul;55:70-81. https://pubmed.ncbi.nlm.nih.gov/26472019/

Solubility Data

	Solvent	Max Conc. mg/mL	Max Conc. mM
Solubility
	DMF	20.0	47.01
	DMSO	15.0	35.26
	Ethanol	20.0	47.01

Preparing Stock Solutions

The following data is based on the product molecular weight 425.43 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:	1. Cheng F, Twardowski L, Fehr S, Aner C, Schaeffeler E, Joos T, Knorpp T, Dorweiler B, Laufer S, Schwab M, Torzewski M. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis. FASEB J. 2017 Feb;31(2):674-686. doi: 10.1096/fj.201600669R. Epub 2016 Nov 8. PMID: 27871059. 2. Taves S, Berta T, Liu DL, Gan S, Chen G, Kim YH, Van de Ven T, Laufer S, Ji RR. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord. Brain Behav Immun. 2016 Jul;55:70-81. doi: 10.1016/j.bbi.2015.10.006. Epub 2015 Oct 19. PMID: 26472019; PMCID: PMC5502100. 3. Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, Grütter C, Werz O, Rauh D, Stehle T, Laufer SA. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2011 Dec 25;8(2):141-3. doi: 10.1038/nchembio.761. PMID: 22198732.
In vitro protocol:	1. Cheng F, Twardowski L, Fehr S, Aner C, Schaeffeler E, Joos T, Knorpp T, Dorweiler B, Laufer S, Schwab M, Torzewski M. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis. FASEB J. 2017 Feb;31(2):674-686. doi: 10.1096/fj.201600669R. Epub 2016 Nov 8. PMID: 27871059.
In vivo protocol:	1. Taves S, Berta T, Liu DL, Gan S, Chen G, Kim YH, Van de Ven T, Laufer S, Ji RR. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord. Brain Behav Immun. 2016 Jul;55:70-81. doi: 10.1016/j.bbi.2015.10.006. Epub 2015 Oct 19. PMID: 26472019; PMCID: PMC5502100. 2. Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, Grütter C, Werz O, Rauh D, Stehle T, Laufer SA. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2011 Dec 25;8(2):141-3. doi: 10.1038/nchembio.761. PMID: 22198732.

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1: Walter NM, Wentsch HK, Bührmann M, Bauer SM, Döring E, Mayer-Wrangowski S, Sievers-Engler A, Willemsen-Seegers N, Zaman G, Buijsman R, Lämmerhofer M, Rauh D, Laufer SA. Design, Synthesis and Biological Evaluation of Novel Type I½ p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency and Prolonged Target Residence Time by Interfering with the R Spine. J Med Chem. 2017 Aug 23. doi: 10.1021/acs.jmedchem.7b00745. [Epub ahead of print] PubMed PMID: 28834431.

2: Al-Maghout T, Pelzl L, Sahu I, Sukkar B, Hosseinzadeh Z, Gutti R, Laufer S, Voelkl J, Pieske B, Gawaz M, Lang F. P38 Kinase, SGK1 and NF-κB Dependent Up-Regulation of Na+/Ca2+ Exchanger Expression and Activity Following TGFß1 Treatment of Megakaryocytes. Cell Physiol Biochem. 2017 Aug 15;42(6):2169-2181. doi: 10.1159/000479992. [Epub ahead of print] PubMed PMID: 28813704.

3: Wentsch HK, Walter NM, Bührmann M, Mayer-Wrangowski S, Rauh D, Zaman GJR, Willemsen-Seegers N, Buijsman RC, Henning M, Dauch D, Zender L, Laufer S. Optimized Target Residence Time: Type I1/2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine. Angew Chem Int Ed Engl. 2017 May 2;56(19):5363-5367. doi: 10.1002/anie.201701185. Epub 2017 Apr 11. PubMed PMID: 28397331.

4: Cheng F, Twardowski L, Fehr S, Aner C, Schaeffeler E, Joos T, Knorpp T, Dorweiler B, Laufer S, Schwab M, Torzewski M. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis. FASEB J. 2017 Feb;31(2):674-686. doi: 10.1096/fj.201600669R. Epub 2016 Nov 8. PubMed PMID: 27871059.

5: Signoretto E, Laufer SA, Lang F. Stimulating Effect of Sclareol on Suicidal Death of Human Erythrocytes. Cell Physiol Biochem. 2016;39(2):554-64. doi: 10.1159/000445647. Epub 2016 Jul 11. PubMed PMID: 27395049.

6: Yan J, Schmid E, Almilaji A, Shumilina E, Borst O, Laufer S, Gawaz M, Lang F. Effect of TGFβ on calcium signaling in megakaryocytes. Biochem Biophys Res Commun. 2015 May 22;461(1):8-13. doi: 10.1016/j.bbrc.2015.03.159. Epub 2015 Apr 4. PubMed PMID: 25849886.

7: Koeberle A, Pergola C, Shindou H, Koeberle SC, Shimizu T, Laufer SA, Werz O. Role of p38 mitogen-activated protein kinase in linking stearoyl-CoA desaturase-1 activity with endoplasmic reticulum homeostasis. FASEB J. 2015 Jun;29(6):2439-49. doi: 10.1096/fj.14-268474. Epub 2015 Feb 12. PubMed PMID: 25678624.

8: Zhao ZW, Abendroth DK, Zhou ZC, Liu YZ, Pan FM, Ge JJ. Anti-inflammatory and anti-proliferative effects of CBS3830 in arterialized vein grafts in rats. Immunopharmacol Immunotoxicol. 2014 Dec;36(6):397-403. doi: 10.3109/08923973.2014.956754. Epub 2014 Sep 10. PubMed PMID: 25204222.

9: Hosseinzadeh Z, Schmid E, Shumilina E, Laufer S, Borst O, Gawaz M, Lang F. Effect of TGFβ on Na+/K+ ATPase activity in megakaryocytes. Biochem Biophys Res Commun. 2014 Sep 26;452(3):537-41. doi: 10.1016/j.bbrc.2014.08.093. Epub 2014 Aug 27. PubMed PMID: 25168590.

10: Borst O, Walker B, Münzer P, Russo A, Schmid E, Faggio C, Bigalke B, Laufer S, Gawaz M, Lang F. Skepinone-L, a novel potent and highly selective inhibitor of p38 MAP kinase, effectively impairs platelet activation and thrombus formation. Cell Physiol Biochem. 2013;31(6):914-24. doi: 10.1159/000350110. Epub 2013 Jun 18. PubMed PMID: 23817201.

11: Fischer S, Wentsch HK, Mayer-Wrangowski SC, Zimmermann M, Bauer SM, Storch K, Niess R, Koeberle SC, Grütter C, Boeckler FM, Rauh D, Laufer SA. Dibenzosuberones as p38 mitogen-activated protein kinase inhibitors with low ATP competitiveness and outstanding whole blood activity. J Med Chem. 2013 Jan 10;56(1):241-53. doi: 10.1021/jm301539x. Epub 2012 Dec 27. PubMed PMID: 23270382.

12: Koeberle SC, Fischer S, Schollmeyer D, Schattel V, Grütter C, Rauh D, Laufer SA. Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase. J Med Chem. 2012 Jun 28;55(12):5868-77. doi: 10.1021/jm300327h. Epub 2012 Jun 15. PubMed PMID: 22676210.

13: Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, Grütter C, Werz O, Rauh D, Stehle T, Laufer SA. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2011 Dec 25;8(2):141-3. doi: 10.1038/nchembio.761. PubMed PMID: 22198732.

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