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{{Short description|Chemical compound}}
{{drugbox
{{Use dmy dates|date=March 2020}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 444926440
| IUPAC_name = 6--''N''-(2,2-dimethylpropyl)pyridine-3-carboxamide
| image = Losmapimod.svg

<!--Clinical data-->
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = Investigational New Drug
| legal_status =
| routes_of_administration =

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =

<!--Identifiers-->
| IUPHAR_ligand = 7835
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 585543-15-3
| ATC_prefix =
| ATC_suffix =
| PubChem = 11552706
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = F2DQF16BXE | UNII = F2DQF16BXE
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| verifiedrevid = 437173959
| ChEMBL = 1088752
| IUPAC_name = 6--N-(2,2-dimethylpropyl)pyridine-3-carboxamide
| KEGG_Ref = {{keggcite|changed|kegg}}
| image = Losmapimod_structure.png
| KEGG = D09639
| width = 200
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| CAS_number =
| ATC_prefix = | ChemSpiderID = 9727484

| ATC_suffix =
<!--Chemical data-->
| PubChem = 11552706
| C=22 | H=26 | F=1 |N=3 | O=2
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| smiles = C3CC3NC(=O)c(cc(F)c1C)cc1-c(cc2)ncc2C(=O)NCC(C)(C)C
| DrugBank =
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| C=22|H=26|F=1|N=3|O=2
| StdInChI = 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)
| molecular_weight = 383.458 g/mol
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| smiles = C3CC3NC(=O)c(cc(F)c1C)cc1-c(cc2)ncc2C(=O)NCC(C)(C)C
| StdInChIKey = KKYABQBFGDZVNQ-UHFFFAOYSA-N
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category=
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = investigational new drug
| routes_of_administration =
}} }}


'''Losmapimod''' ('''GW856553X''') is an ] that reached stage III clinical trials for multiple medical conditions, but did not prove efficacy. It was most recently ] by ] for the treatment of ] (FSHD). Losmapimod selectively inhibits ]s ] (MAPKs), which are modulators of ] expression and mediators of ].<ref name="pmid19772287">{{cite journal | vauthors = Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, Patel VK, Smee PA, Somers DO, Vitulli G, Walker AL | display-authors = 6 | title = p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 20 | pages = 6257–69 | date = October 2009 | pmid = 19772287 | doi = 10.1021/jm9004779 }}</ref>
'''Losmapimod''' ('''GW856553X''') is a drug developed by ] which acts as a selective inhibitor of the ] family known as ].<ref>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}}</ref> Inhibiting these enzymes has been shown to produce ] and ] effects in animal studies, with the mechanism thought to involve increased ]<ref>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}}</ref> probably related to ] release. Losmapimod has completed Phase II human ] for the treatment of ] although its safety and efficacy have yet to be proven in further trials.<ref></ref>

== Historical Investigations ==
Losmapimod was ] and unsuccessfully ] by GSK for treating multiple medical conditions. Despite failing to prove efficacy, GSK clinical trials showed that losmapimod is generally well tolerated across more than 3,500 subjects.<ref name="IPO statement">{{cite web |title=FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 FULCRUM THERAPEUTICS, INC. |url=https://www.sec.gov/Archives/edgar/data/1680581/000104746919004014/a2239182zs-1a.htm |website=www.sec.gov |publisher=Securities and Exchange Commission |access-date=26 October 2019}}</ref><ref name="COPD Trial 1 publication">{{cite journal | vauthors = Watz H, Barnacle H, Hartley BF, Chan R | title = Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial | journal = The Lancet. Respiratory Medicine | volume = 2 | issue = 1 | pages = 63–72 | date = January 2014 | pmid = 24461903 | doi = 10.1016/S2213-2600(13)70200-5 }}</ref><ref name="COPD Trial 2 publication">{{cite journal | vauthors = Fisk M, Cheriyan J, Mohan D, Forman J, Mäki-Petäjä KM, McEniery CM, Fuld J, Rudd JH, Hopkinson NS, Lomas DA, Cockcroft JR, Tal-Singer R, Polkey MI, Wilkinson IB | display-authors = 6 | title = The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial | journal = PLOS ONE | volume = 13 | issue = 3 | pages = e0194197 | date = 2018 | pmid = 29566026 | pmc = 5863984 | doi = 10.1371/journal.pone.0194197 | bibcode = 2018PLoSO..1394197F | doi-access = free }}</ref>

GSK investigated losmapimod as a therapeutic for patients post-] (heart attack). Despite phase II clinical trials<ref>{{ClinicalTrialsGov|NCT00474864|Study To Evaluate The Effects Of GW856553 On Endothelial Function/Vascular Compliance In Subjects With Dyslipidaemia.}}</ref><ref>{{ClinicalTrialsGov|NCT00633022|A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging}}</ref><ref>{{ClinicalTrialsGov|NCT00910962|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)}}</ref><ref name="pmid21262998">{{cite journal | vauthors = Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Mäki-Petäjä KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB | s2cid = 25095165 | display-authors = 6 | title = Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia | journal = Circulation | volume = 123 | issue = 5 | pages = 515–23 | date = February 2011 | pmid = 21262998 | doi = 10.1161/CIRCULATIONAHA.110.971986 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, Collier DJ, Marber MS, Choudhury RP, Fayad ZA, Tawakol A, Gleeson FV, Lepore JJ, Davis B, Willette RN, Wilkinson IB, Sprecher DL, Cheriyan J | display-authors = 6 | title = Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis | journal = JACC. Cardiovascular Imaging | volume = 5 | issue = 9 | pages = 911–22 | date = September 2012 | pmid = 22974804 | doi = 10.1016/j.jcmg.2012.02.016 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, Cai G, de Winter RJ, Hamm CW, Heitner JF, Kim R, Lerman A, Patel MR, Tanguay JF, Lepore JJ, Al-Khalidi HR, Sprecher DL, Granger CB | s2cid = 38041584 | display-authors = 6 | title = Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial | journal = Lancet | volume = 384 | issue = 9949 | pages = 1187–95 | date = September 2014 | pmid = 24930728 | doi = 10.1016/S0140-6736(14)60417-7 }}</ref> the phase IIIA clinical trial (LATITUDE)<ref>{{ClinicalTrialsGov|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)}}</ref> failed to show significantly improved clinical outcomes.<ref>{{cite journal | vauthors = O'Donoghue ML, Glaser R, Cavender MA, Aylward PE, Bonaca MP, Budaj A, Davies RY, Dellborg M, Fox KA, Gutierrez JA, Hamm C, Kiss RG, Kovar F, Kuder JF, Im KA, Lepore JJ, Lopez-Sendon JL, Ophuis TO, Parkhomenko A, Shannon JB, Spinar J, Tanguay JF, Ruda M, Steg PG, Theroux P, Wiviott SD, Laws I, Sabatine MS, Morrow DA | display-authors = 6 | title = Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial | journal = JAMA | volume = 315 | issue = 15 | pages = 1591–9 | date = April 2016 | pmid = 27043082 | doi = 10.1001/jama.2016.3609 | doi-access = free }}</ref> In October 2015 GSK announced cancelling the planned phase IIIB trial, but would "evaluate all options for future development."<ref>{{cite news |title=GSK provides update on LATITUDE-TIMI 60 (losmapimod cardiovascular study) |url=https://www.gsk.com/en-gb/media/press-releases/gsk-provides-update-on-latitude-timi-60-losmapimod-cardiovascular-study/ |access-date=12 August 2019 |work=GSK |date=27 October 2015}}</ref>

GSK investigated losmapimod as a therapeutic for COPD, but multiple phase II clinical trials<ref name="COPD Trial 1">{{ClinicalTrialsGov|NCT01218126|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)}}</ref><ref name="COPD Trial 2">{{ClinicalTrialsGov|NCT01541852|Losmapimod in Chronic Obstructive Pulmonary Disease Patients Stratified by Fibrinogen. (EVOLUTION)}}</ref><ref name="COPD Trial 3">{{ClinicalTrialsGov|NCT02299375|Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)}}</ref> failed to show that losmapimod improves exercise tolerance,<ref name="COPD Trial 1 publication" /> lung function,<ref name="COPD Trial 1 publication" /> arterial inflammation,<ref name="COPD Trial 2 publication" /> endothelial function,<ref name="COPD Trial 2 publication" /> or rate of COPD exacerbations<ref name="COPD Trial 3 publication">{{cite journal | vauthors = Pascoe S, Costa M, Marks-Konczalik J, McKie E, Yang S, Scherbovsky PS | title = Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD | journal = Respiratory Medicine | volume = 130 | pages = 20–26 | date = September 2017 | pmid = 29206629 | doi = 10.1016/j.rmed.2017.07.002 | doi-access = free }}</ref> in subjects with COPD. GSK terminated development of losmapimod for COPD in 2016.<ref name="COPD News BioSpace">{{cite news |last1=Keown |first1=Alex | name-list-style = vanc |title=GlaxoSmithKline Terminates Development of Losmapimod for COPD |url=https://www.biospace.com/article/glaxosmithkline-terminates-development-of-losmapimod-for-copd-/ |access-date=11 August 2019 |publisher=BioSpace |date=Oct 26, 2016}}</ref><ref name="COPD News FierceBiotech">{{cite news |last1=Lawrence |first1=Stacy | name-list-style = vanc |title=GSK drops a pair of late-stage candidates in COPD, HIV |url=https://www.fiercebiotech.com/biotech/gsk-drops-a-pair-late-stage-candidates-copd-hiv |access-date=11 August 2019 |publisher=FierceBiotech |date=Oct 26, 2016 |language=en}}</ref>

GSK investigated losmapimod as a therapeutic for major depressive disorder (MDD) on the basis of depression being correlated with elevated pro-inflammatory cytokines.<ref name="Depression">{{cite journal | vauthors = Inamdar A, Merlo-Pich E, Gee M, Makumi C, Mistry P, Robertson J, Steinberg E, Zamuner S, Learned S, Alexander R, Ratti E | s2cid = 1370216 | display-authors = 6 | title = Evaluation of antidepressant properties of the p38 MAP kinase inhibitor losmapimod (GW856553) in Major Depressive Disorder: Results from two randomised, placebo-controlled, double-blind, multicentre studies using a Bayesian approach | journal = Journal of Psychopharmacology | volume = 28 | issue = 6 | pages = 570–81 | date = June 2014 | pmid = 24699061 | doi = 10.1177/0269881114529377 }}</ref> Phase II clinical trials<ref name="Depression Trial Terminated">{{ClinicalTrialsGov|NCT00569062|A Study of GW856553X For the Treatment of Depression}}</ref><ref name="Depression Trial Completed">{{ClinicalTrialsGov|NCT00976560|Clinical Study to Test a New Drug to Treat Major Depression}}</ref> failed to show a significant improvement in depression symptoms and biomarkers.<ref name="Depression" />

In 2019 Fulcrum therapeutics acquired from GSK the rights to losmapimod.<ref>{{cite web | url = https://www.biospace.com/article/releases/fulcrum-therapeutics-acquires-global-rights-to-losmapimod-a-potential-disease-modifying-therapy-for-facioscapulohumeral-muscular-dystrophy/ | title = Fulcrum Therapeutics Acquires Global Rights to Losmapimod, a Potential Disease-Modifying Therapy for Facioscapulohumeral Muscular Dystrophy | publisher = BioSpace | date = 23 April 2019 }}</ref> Fulcrum identified p38α/β MAPK inhibitors as potent suppressors of DUX4 expression, the de-suppression of which is accepted as the cause FSHD, and then chose to develop losmapimod for FSHD due to "substantial and attractive preclinical and clinical data" from previous ] (GSK) clinical trials.<ref name="IPO statement"/> Although a 2021 phase IIb clinical trial showed slowing of muscle deterioration,<ref>{{cite web |title=ReDUX4 trial result exceeds expectations |url=https://www.fshdsociety.org/2021/06/24/redux4-trial-result-exceeds-expectations/ |website=FSHD Society |access-date=26 June 2021 |archive-url=https://web.archive.org/web/20210626171442/https://www.fshdsociety.org/2021/06/24/redux4-trial-result-exceeds-expectations/ |archive-date=26 June 2021 |location=Wayback Machine |date=2021-06-24}}</ref><ref>{{cite web |title=Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) |url=https://clinicaltrials.gov/ct2/show/NCT04003974?term=losmapimod&rank=3 |website=ClinicalTrials.gov |publisher=United States National Library of Medicine |access-date=12 August 2019 |language=en}}</ref><ref>{{ClinicalTrialsGov|NCT04003974|Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) (FSHD)}}</ref><ref>{{cite news |title=Fulcrum's losmapimod fails interim analysis in muscle wasting trial |url=https://www.fiercebiotech.com/biotech/fulcrum-s-losmapimod-fails-interim-analysis-muscle-wasting-trial |work=FierceBiotech |language=en}}</ref><ref>{{ClinicalTrialsGov|NCT04004000|Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1}}</ref> a 2024 phase III clinical trial failed to demonstrate efficacy.{{Citation needed|date=September 2024}}


== References == == References ==
{{Reflist}} {{Reflist}}


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