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Losmapimod

p38 MAPK inhibitor, orally active CAS# 585543-15-3

Losmapimod

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Losmapimod

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Chemical Properties of Losmapimod

Cas No. 585543-15-3 SDF Download SDF
PubChem ID 11552706 Appearance Powder
Formula C22H26FN3O2 M.Wt 383.46
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GSK-AHAB; GW856553X; SB856553
Solubility DMSO : ≥ 58 mg/mL (151.25 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide
SMILES CC1=C(C=C(C=C1C2=NC=C(C=C2)C(=O)NCC(C)(C)C)C(=O)NC3CC3)F
Standard InChIKey KKYABQBFGDZVNQ-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Losmapimod

DescriptionLosmapimod (GW856553X) is a selective, potent, and orally active inhibitor of p38 MAPK with a pKi values of 8.1 and 7.6 for p38α and p38β, respectively.
Targetsp38αp38β    
IC50(pKi=8.1)(pKi=7.6)    

Protocol

Animal Administration [1]
Male SHR-SPs (n=70) are randomly assigned according to body weight into five groups (n=14 per group): normal diet controls (ND), high salt-fat diet controls (SFD), SFD + GSK-AHAB (1.2 mg/kg/day), and SFD + GSK-AHAB (12 mg/kg/day) and SFD + rofecoxib (18 mg/kg/day). All drugs are administered in the diet by mixing with the SFD. A subgroup of animals from each group (n=6 per group) are anesthetized with isoflurane and surgically instrumented with radiotelemetry units for the conscious measurement of mean arterial blood pressure and heart rate. These animals are allowed to recover for at least 7 days before the start of the study.

References:
[1]. Willette RN, et al. 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. [2]. Zhang XM, et al. Suppression of mitochondrial fission in experimental cerebral ischemia: The potential neuroprotective target of p38 MAPK inhibition. Neurochem Int. 2015 Nov;90:1-8.

Losmapimod Dilution Calculator

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Preparing Stock Solutions of Losmapimod

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6078 mL 13.0392 mL 26.0783 mL 52.1567 mL 65.1958 mL
5 mM 0.5216 mL 2.6078 mL 5.2157 mL 10.4313 mL 13.0392 mL
10 mM 0.2608 mL 1.3039 mL 2.6078 mL 5.2157 mL 6.5196 mL
50 mM 0.0522 mL 0.2608 mL 0.5216 mL 1.0431 mL 1.3039 mL
100 mM 0.0261 mL 0.1304 mL 0.2608 mL 0.5216 mL 0.652 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Losmapimod

Losmapimod (GW856553, GW856553X, GSK-AHAB) is a potent and selective inhibitor of p38 MAPK with pKi values of 8.1 and 7.6 for p38α and p38β, respectively [1].

p38 mitogen-activated protein kinase (p38 MAPK) is an intracellular signaling kinase and plays an important role in regulating transcription and translation of the inflammatory response in macrophages and endothelial cells [2].

Losmapimod is an orally active p38 MAPK inhibitor. In the spontaneously hypertensive stroke-prone rats (SHR-SPs) with a salt-fat diet, GSK-AHAB significantly improved survival and renal function in a dose-dependent way and induced vascular relaxation. Also, GSK-AHAB attenuated hypertension, cardiac remodeling, dyslipidemia, plasma renin activity (PRA), interleukin-1 (IL-1) and aldosterone [1]. In patients with hypercholesterolemia, losmapimod improved acetylcholine, sodium nitroprusside and NG-monomethyl-L-arginine (L-NMMA) responses by 25%, 20% and 10%, respectively. Also, losmapimod reduced C-reactive protein (a systemic inflammatory marker) by 57%. These results suggested that losmapimod improved NO-mediated vasodilatation and inhibited inflammation [2]. In patients with chronic obstructive pulmonary disease (COPD), losmapimod (7.5 mg twice daily) reduced plasma fibrinogen by 11% and was well tolerated [3].

References:
[1].  Willette RN, Eybye ME, Olzinski AR, et al. Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. J Pharmacol Exp Ther, 2009, 330(3): 964-970.
[2].  Cheriyan J, Webb AJ, Sarov-Blat L, et al. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation., 2011, 123(5): 515-523.
[3].  Lomas DA, Lipson DA, Miller BE, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol, 2012, 52(3): 416-424.

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References on Losmapimod

Emerging treatment options to improve cardiovascular outcomes in patients with acute coronary syndrome: focus on losmapimod.[Pubmed:26273189]

Drug Des Devel Ther. 2015 Aug 5;9:4279-86.

Each year, despite optimal use of recommended acute and secondary prevention therapies, 4%-5% of patients with acute coronary syndrome (ACS) experience relapse of ACS or other cardiovascular events including stroke, heart failure, or sudden cardiac death after the index ACS. The sudden atherosclerotic plaque rupture leading to an ACS event is often accompanied by inflammation, which is thought to be a key pathogenic pathway to these excess cardiovascular events. Losmapimod is a novel, oral p38 mitogen-activated protein kinase (MAPK) inhibitor that targets MAPKs activated in macrophages, myocardium, and endothelial cells that occur as a part of global coronary vascular inflammation following plaque rupture. This review aims to 1) discuss the pathophysiological pathways through which p38 MAPKs may play key roles in initiation and progression of inflammatory disease and how Losmapimod is thought to counteract these p38 MAPKs, and 2) to describe the efficacy and safety data for Losmapimod obtained from preclinical studies and randomized controlled trials that support the hypothesis that it has promise as a treatment for patients with ACS.

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial.[Pubmed:27043082]

JAMA. 2016 Apr 19;315(15):1591-9.

IMPORTANCE: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor Losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE: To evaluate the efficacy and safety of Losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS: LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS: Patients were randomized to either twice-daily Losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS: In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with Losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with Losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE: Among patients with acute MI, use of Losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02145468.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod in healthy Japanese volunteers.[Pubmed:27136906]

Clin Pharmacol Drug Dev. 2015 Jul;4(4):262-9.

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of Losmapimod and its metabolite GSK198602 following single and repeat doses of oral Losmapimod in healthy Japanese volunteers. Subjects (n = 41) received single oral doses of Losmapimod (2.5, 7.5, 20 mg) or matching placebo on 3 separate days (n = 20) or Losmapimod 7.5 mg or matching placebo twice daily for 14 days (n = 21). Assessments included maximum observed plasma concentration (Cmax ), time to Cmax (Tmax ), apparent terminal-phase half-life (t1/ )2 , area under the curve (AUC), and change in C-reactive protein and phosphorylated heat shock protein 27 levels. No serious adverse events occurred during the study, and there were no safety concerns regarding clinical laboratory parameters, 12-lead electrocardiogram, or vital signs. The Losmapimod Tmax was 3-4 hours, and the mean t1/2 was approximately 7.9-9.0 hours, with no appreciable difference in Tmax and apparent clearance following oral dosing between dosing regimens. Single and repeat oral doses of Losmapimod were well tolerated in healthy Japanese volunteers. The Tmax of GSK198602 was similar to and t1/2 was slightly longer than those of Losmapimod. Approximate dose-proportional increases in exposure to Losmapimod and GSK198602 were observed in AUC with single-dose administration. Repeat-dose trough concentrations reached steady state within 2 days, with an observed accumulation ratio of 1.56 and 1.91 for Losmapimod and GSK198602, respectively.

Description

Losmapimod is a selective, potent, and orally active p38 MAPK inhibitor with pKis of 8.1 and 7.6 for p38α and p38β, respectively.

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