Losmapimod

Losmapimod

Legal status
Legal status	investigational new drug
Identifiers
IUPAC name 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide
CAS Number	585543-15-3
PubChem (CID)	11552706
IUPHAR/BPS	7835
ChemSpider	9727484
UNII	F2DQF16BXE
KEGG	D09639
ChEMBL	CHEMBL1088752
ECHA InfoCard	100.158.124
Chemical and physical data
Formula	C22H26FN3O2
Molar mass	383.458 g/mol
3D model (Jmol)	Interactive image
SMILES C3CC3NC(=O)c(cc(F)c1C)cc1-c(cc2)ncc2C(=O)NCC(C)(C)C
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) Key:KKYABQBFGDZVNQ-UHFFFAOYSA-N
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Losmapimod (GW856553X) is a drug developed by GlaxoSmithKline which acts as a selective inhibitor of the enzyme family known as p38 mitogen-activated protein kinases.^[1]

p38 mitogen-activated protein kinases are mediators of inflammation. A Phase II human clinical trial for the treatment of COPD (chronic obstructive pulmonary disease)^[2] 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^[3] probably related to BDNF release. Losmapimod has completed Phase II human clinical trials for the treatment of depression although its safety and efficacy have yet to be proven in further trials.^[4]

Losmapimod is also being studied for cardiovascular disease.^[5] A Phase II trial (LATITUDE) to study its effects in myocardial infarction (heart attack) has been stopped in January 2016 because of disappointing results in phase A of the trial.^[6]

References

1. Aston N, Bamborough P, Buckton J, Edwards C, Holmes D, Jones K, Patel V, Smee P, Somers D, Vitulli G, Walker A. p38α Mitogen-Activated Protein Kinase Inhibitors: Optimization of a Series of Biphenylamides to Give a Molecule Suitable for Clinical Progression. Journal of Medicinal Chemistry 2009, 52(20), 6257. doi:10.1021/jm9004779
2. Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Losmapimod Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Subjects With Chronic Obstructive Pulmonary Disease (COPD)
3. Noh JS, Kang HJ, Kim YE, Sohn S, Chung YK, Kim SU, Gwag BJ. Haloperidol-Induced Neuronal Apoptosis: role of p38 and c-Jun-NH(2)-terminal protein kinase. Journal of Neurochemistry 2000, 75(6), 2327. PMID 11080184 doi:10.1046/j.1471-4159.2000.0752327.x
4. A Study of GW856553X For the Treatment of Depression
5. Cheriyan et al., Circulation 2011, 123(5), 515-523. Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia doi:10.1161/CIRCULATIONAHA.110.971986
6. A Study to Evaluate the Safety of 12 Weeks of Dosing With GW856553 and Its Effects on Inflammatory Markers, Infarct Size, and Cardiac Function in Subjects With Myocardial Infarction Without ST-segment Elevation (Solstice)