losmapimod   Click here for help

GtoPdb Ligand ID: 7835

Synonyms: GS856553 | GW856553
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Losmapimod is a p38 mitogen-activated kinase α/β inhibitor. It was originally developed by GlaxoSmithKline for cardiovascular disease, but this failed to show efficacy. Fulcrum acquired the drug and are repurposing it for the treatment of the progressive muscle wasting disorder facioscapulohumeral muscular dystrophy (FSHD) based on evidence that p38α regulates expression of the FSHD-related gene DUX4 [4-5].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 8
Topological polar surface area 71.09
Molecular weight 383.2
XLogP 4.01
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES O=C(c1ccc(nc1)c1cc(cc(c1C)F)C(=O)NC1CC1)NCC(C)(C)C
Isomeric SMILES O=C(c1ccc(nc1)c1cc(cc(c1C)F)C(=O)NC1CC1)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)
InChI Key KKYABQBFGDZVNQ-UHFFFAOYSA-N
References
1. Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, Patel VK, Smee PA, Somers DO, Vitulli G et al.. (2009)
p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.
J Med Chem, 52 (20): 6257-69. [PMID:19772287]
2. O'Donoghue ML, Glaser R, Aylward PE, Cavender MA, Crisp A, Fox KA, Laws I, Lopez-Sendon JL, Steg PG, Theroux P et al.. (2015)
Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial.
Am Heart J, 169 (5): 622-630.e6. [PMID:25965709]
3. O'Donoghue ML, Glaser R, Cavender MA, Aylward PE, Bonaca MP, Budaj A, Davies RY, Dellborg M, Fox KA, Gutierrez JA et al.. (2016)
Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial.
JAMA, 315 (15): 1591-9. [PMID:27043082]
4. Oliva J, Galasinski S, Richey A, Campbell AE, Meyers MJ, Modi N, Zhong JW, Tawil R, Tapscott SJ, Sverdrup FM. (2019)
Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy.
J Pharmacol Exp Ther, 370 (2): 219-230. [PMID:31189728]
5. Rojas LA, Valentine E, Accorsi A, Maglio J, Shen N, Robertson A, Kazmirski S, Rahl P, Tawil R, Cadavid D et al.. (2020)
p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy.
J Pharmacol Exp Ther, 374 (3): 489-498. [PMID:32576599]