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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2D Structure
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Physico-chemical Properties
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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
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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)
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]