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
No information available.
Summary of Clinical Use Click here for help
Losmapimod has been evaluated in clinical trials for cardiovascular disease [2], inflammatory conditions and a muscle wasting disease [4-5]. It has failed to provide significant efficacy in trials for cardiovascular disease, and has failed to meet the primary endpoint in a Phase 2 facioscapulohumeral muscular dystrophy (FSHD) study (NCT04264442).
Mechanism Of Action and Pharmacodynamic Effects Click here for help
p38alpha MAP kinase is a key anti-inflammatory target as it influences the biosynthesis of pro-inflammatory cytokines TNFα and IL-1β at a translational and transcriptional level. Losmapimod is a novel p38alpha MAP kinase inhibitor being investigated for its anti-inflammatory action.
The rationale for using losmapimod as a treatment for ACS, a condition which includes heart attack, was evidence that the inflammatory response to ACS is central to the development of plaque instability. By inhibiting p38 mitogen-activated protein kinase (MAPK) it was hypothesised that losmapimod might stabilize atherosclerotic plaques, reducing the risk of subsequent plaque rupture and thereby indirectly improving vascular function and preventing subsequent thrombosis. Unfortunately this hypothesis did not translate to clinical efficacy in humans.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02145468 A Phase 3 Clinical Outcomes Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting With Acute Coronary Syndrome Treated With Losmapimod Compared to Placebo (LATITUDE-TIMI 60) Phase 3 Interventional GlaxoSmithKline Losmapimod fared no better than placebo and not reduce the risk of major ischemic cardiovascular events in this study. It was not progressed further. 3
NCT01541852 Losmapimod in Chronic Obstructive Pulmonary Disease Patients Stratified by Fibrinogen. Phase 2 Interventional Cambridge University Hospitals NHS Foundation Trust
NCT02000440 A Phase II, Repeat Dose, Proof of Mechanism Study of Losmapimod to Reduce Proteinuria in Patients With Focal Segmental Glomerulosclerosis (FSGS) Phase 2 Interventional GlaxoSmithKline
NCT04003974 Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) Phase 2 Interventional Fulcrum Therapeutics
NCT04264442 Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) With Open-Label Extension (OLE) Phase 2 Interventional Fulcrum Therapeutics ReDUX4 study: testing the hypothesis that losmapimod might block expression of the transcriptional activator DUX4, as a mechanism for treating FSHD. Despite having no effect on DUX4 expression after 48 weeks of losmapimod treatment, other signals of potential benefit have been detected and as of June 2021 Fulcrum have committed to continuing development in FSHD.