Losmapimod | GW856553 | 585543-15-3 | p38 MAPK inhibitor

MedKoo Cat#: 510231 | Name: Losmapimod

Description:

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

Losmapimod, also know as GW856553 or GW856553X or GSK-AHAB, is a drug developed by GlaxoSmithKline which acts as a selective inhibitor of the enzyme family known as p38 mitogen-activated protein kinases. p38 mitogen-activated protein kinases are mediators of inflammation. A Phase II human clinical trial for the treatment of COPD (chronic obstructive pulmonary disease) is underway. Inhibiting these enzymes has been shown to produce antidepressant and antipsychotic effects in animal studies, with the mechanism thought to involve increased neurogenesis probably related to BDNF release.

Chemical Structure

Losmapimod

CAS#585543-15-3

Theoretical Analysis

MedKoo Cat#: 510231

Name: Losmapimod

CAS#: 585543-15-3

Chemical Formula: C22H26FN3O2

Exact Mass: 383.2009

Molecular Weight: 383.46

Elemental Analysis: C, 68.91; H, 6.83; F, 4.95; N, 10.96; O, 8.34

Price and Availability

Size	Price	Availability
10mg	USD 110.00	Ready to ship
25mg	USD 220.00	Ready to ship
50mg	USD 400.00	Ready to ship
100mg	USD 700.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship

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Related CAS #

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Synonym

Losmapimod; GW856553; GW-856553; GW 856553; GSK-AHAB;

IUPAC/Chemical Name

6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide.

InChi Key

KKYABQBFGDZVNQ-UHFFFAOYSA-N

InChi Code

InChI=1S/C22H26FN3O2/c1-13-17(9-15(10-18(13)23)21(28)26-16-6-7-16)19-8-5-14(11-24-19)20(27)25-12-22(2,3)4/h5,8-11,16H,6-7,12H2,1-4H3,(H,25,27)(H,26,28)

SMILES Code

O=C(C1=CC=C(C2=CC(C(NC3CC3)=O)=CC(F)=C2C)N=C1)NCC(C)(C)C

Appearance

white 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, not in water

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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T20D10P10

View CoA: current batch, Lot#A9T08K13

QC Data

View QC data: current batch, Lot#A9T08K13

View QC data: current batch, Lot#T20D10P10

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Losmapimod (GSK-AHAB) is a p38 MAPK inhibitor with pKis of 8.1 and 7.6 for p38α and p38β, respectively.

In vitro activity:

To further examine the detailed mechanism of gefitinib-induced tetraploidization, this study determined p-STAT3, p21 and cyclin D1 expressions after gefitinib and/or losmapimod treatment in gefitinib-resistant cells. Consistent with the results of tetraploidization and p38 MAPK inhibition, Western blotting revealed that phosphorylation of STAT3 and expressions of p21 and cyclin D1 were up-regulated with gefitinib treatment in both resistant cell lines, and that the up-regulations could be inhibited by losmapimod (Fig. 3C). All these findings suggest that gefitinib-induced tetraploidization requires p38 MAPK signaling and could be targeted by p38 MAPK inhibitors. Reference: EBioMedicine. 2018 Feb; 28: 51–61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835564/

In vivo activity:

Neurons were degenerated in CA3 of pilocarpine-induced rats’ hippocampi. Following losmapimod treatment, neuronal cell loss was inhibited compared with the SE group. In addition, the results of the losmapimod-treated group was similar to that of the phenobarbital-treated group (Figure 4 A). These data suggest that losmapimod treatment could rescue the loss of neurons in the CA3 region. Cell apoptosis in the pilocarpine-induced epilepsy group was higher than that in the control group, but losmapimod treatment restrained apoptosis, though the effect was not as effective as it was with phenobarbital (Figure 4 B). Bax and cleaved caspase 3 were upregulated, while Bcl2 was significantly downregulated in the hippocampal tissues of the SE rats. Losmapimod treatment significantly reversed the changes in Bax, Bcl2, and cleaved caspase 3 expression in hippocampal tissues in vivo (Figure 4 C). Reference: Front Pharmacol. 2019; 10: 625. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565798/

	Solvent	mg/mL	mM
Solubility
	DMSO	44.5	116.05
	DMF	30.0	78.24
	Ethanol	46.4	121.11
	Ethanol:PBS (pH 7.2) (1:50)	0.0	0.03

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 383.46 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. Zhang X, Yan F, Tang K, Chen Q, Guo J, Zhu W, He S, Banadyga L, Qiu X, Guo Y. Identification of a clinical compound losmapimod that blocks Lassa virus entry. Antiviral Res. 2019 Jul;167:68-77. doi: 10.1016/j.antiviral.2019.03.014. Epub 2019 Apr 4. PMID: 30953674; PMCID: PMC7111477. 2. Yeung YT, Yin S, Lu B, Fan S, Yang R, Bai R, Zhang C, Bode AM, Liu K, Dong Z. Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. EBioMedicine. 2018 Feb;28:51-61. doi: 10.1016/j.ebiom.2018.01.017. Epub 2018 Feb 2. PMID: 29398601; PMCID: PMC5835564. 3. Li M, Cui L, Feng X, Wang C, Zhang Y, Wang L, Ding Y, Zhao T. Losmapimod Protected Epileptic Rats From Hippocampal Neuron Damage Through Inhibition of the MAPK Pathway. Front Pharmacol. 2019 Jun 7;10:625. doi: 10.3389/fphar.2019.00625. PMID: 31231220; PMCID: PMC6565798. 4. Yeung YT, Yin S, Lu B, Fan S, Yang R, Bai R, Zhang C, Bode AM, Liu K, Dong Z. Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. EBioMedicine. 2018 Feb;28:51-61. doi: 10.1016/j.ebiom.2018.01.017. Epub 2018 Feb 2. PMID: 29398601; PMCID: PMC5835564.

In vitro protocol:

In vivo protocol:

1. Li M, Cui L, Feng X, Wang C, Zhang Y, Wang L, Ding Y, Zhao T. Losmapimod Protected Epileptic Rats From Hippocampal Neuron Damage Through Inhibition of the MAPK Pathway. Front Pharmacol. 2019 Jun 7;10:625. doi: 10.3389/fphar.2019.00625. PMID: 31231220; PMCID: PMC6565798. 2. Yeung YT, Yin S, Lu B, Fan S, Yang R, Bai R, Zhang C, Bode AM, Liu K, Dong Z. Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. EBioMedicine. 2018 Feb;28:51-61. doi: 10.1016/j.ebiom.2018.01.017. Epub 2018 Feb 2. PMID: 29398601; PMCID: PMC5835564.

1: Yang S, Beerahee M. Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials. Eur J Clin Pharmacol. 2013 Jun;69(6):1261-7. doi: 10.1007/s00228-012-1469-1. Epub 2013 Jan 17. PubMed PMID: 23325437. 2: Yang S, Lukey P, Beerahee M, Hoke F. Population pharmacokinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases. Clin Pharmacokinet. 2013 Mar;52(3):187-98. doi: 10.1007/s40262-012-0025-6. PubMed PMID: 23254770. 3: Dewenter M, Vettel C, El-Armouche A. [Losmapimod: a novel drug against cardiovascular diseases?]. Dtsch Med Wochenschr. 2013 Jan;138(1-2):39-42. doi: 10.1055/s-0032-1327368. Epub 2012 Dec 18. Review. German. PubMed PMID: 23250695. 4: Ostenfeld T, Krishen A, Lai RY, Bullman J, Baines AJ, Green J, Anand P, Kelly M. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2013 Jul;17(6):844-57. doi: 10.1002/j.1532-2149.2012.00256.x. Epub 2012 Dec 14. PubMed PMID: 23239139. 5: Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013 Jul;76(1):99-106. doi: 10.1111/bcp.12063. PubMed PMID: 23215699; PubMed Central PMCID: PMC3703232. 6: Melloni C, Sprecher DL, Sarov-Blat L, Patel MR, Heitner JF, Hamm CW, Aylward P, Tanguay JF, DeWinter RJ, Marber MS, Lerman A, Hasselblad V, Granger CB, Newby LK. The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale. Am Heart J. 2012 Nov;164(5):646-653.e3. doi: 10.1016/j.ahj.2012.07.030. Epub 2012 Oct 16. PubMed PMID: 23137494. 7: Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, Collier DJ, Marber MS, Choudhury RP, Fayad ZA, Tawakol A, Gleeson FV, Lepore JJ, Davis B, Willette RN, Wilkinson IB, Sprecher DL, Cheriyan J. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging. 2012 Sep;5(9):911-22. doi: 10.1016/j.jcmg.2012.02.016. PubMed PMID: 22974804. 8: Lomas DA, Lipson DA, Miller BE, Willits L, Keene O, Barnacle H, Barnes NC, Tal-Singer R; Losmapimod Study Investigators. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 2012 Mar;52(3):416-24. doi: 10.1177/0091270010397050. Epub 2011 Nov 16. PubMed PMID: 22090363. 9: Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, MÃ¤ki-PetÃ¤jÃ¤ KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24. PubMed PMID: 21262998. 10: Welchman R. Advances and Progress in Drug Design - SMi's ninth annual meeting. IDrugs. 2010 Apr;13(4):239-42. PubMed PMID: 20373252. 11: Willette RN, Eybye ME, Olzinski AR, Behm DJ, Aiyar N, Maniscalco K, Bentley RG, Coatney RW, Zhao S, Westfall TD, Doe CP. Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. J Pharmacol Exp Ther. 2009 Sep;330(3):964-70. doi: 10.1124/jpet.109.154443. Epub 2009 Jun 25. PubMed PMID: 19556450.