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'''Arimoclomol''' ([[International Nonproprietary Name|INN]], originally codenamed ''' BRX-220''') is an experimental drug developed by [[CytRx|CytRx Corporation]], a biopharmaceutical company based in [[Los Angeles, California]]. The orally administered drug is intended to treat [[amyotrophic lateral sclerosis]] (ALS).<ref name="pmid18551622">{{cite journal |author=Cudkowicz ME, Shefner JM, Simpson E, ''et al.'' |title=Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis |journal=Muscle Nerve |volume=38 |issue=1 |pages=837–44 | |
'''Arimoclomol''' ([[International Nonproprietary Name|INN]], originally codenamed ''' BRX-220''') is an experimental drug developed by [[CytRx|CytRx Corporation]], a biopharmaceutical company based in [[Los Angeles, California]]. The orally administered drug is intended to treat [[amyotrophic lateral sclerosis]] (ALS).<ref name="pmid18551622">{{cite journal |author=Cudkowicz ME, Shefner JM, Simpson E, ''et al.'' |title=Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis |journal=Muscle Nerve |volume=38 |issue=1 |pages=837–44 |date=July 2008 |pmid=18551622 |doi=10.1002/mus.21059}}</ref><ref>{{cite journal |author=Traynor BJ, Bruijn L, Conwit R, ''et al.'' |title=Neuroprotective agents for clinical trials in ALS: a systematic assessment |journal=Neurology |volume=67 |issue=1 |pages=20–7 |date=July 2006 |pmid=16832072 |doi=10.1212/01.wnl.0000223353.34006.54 |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=16832072}}</ref> |
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== Mechanism of action == |
== Mechanism of action == |
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Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of [[chaperone (protein)|molecular chaperones]]. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases. |
Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of [[chaperone (protein)|molecular chaperones]]. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases. |
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Arimoclomol activates the [[heat shock protein|heat shock]] response.<ref name="pmid19183864">{{cite journal |author=Kalmar B, Greensmith L |title=Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects |journal=Cell. Mol. Biol. Lett. |volume=14 |issue=2 |pages=319–35 |year=2009 |pmid=19183864 |doi=10.2478/s11658-009-0002-8}}</ref><ref name="pmid15034571">{{cite journal |author=Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L |title=Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice |journal=Nat. Med. |volume=10 |issue=4 |pages=402–5 | |
Arimoclomol activates the [[heat shock protein|heat shock]] response.<ref name="pmid19183864">{{cite journal |author=Kalmar B, Greensmith L |title=Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects |journal=Cell. Mol. Biol. Lett. |volume=14 |issue=2 |pages=319–35 |year=2009 |pmid=19183864 |doi=10.2478/s11658-009-0002-8}}</ref><ref name="pmid15034571">{{cite journal |author=Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L |title=Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice |journal=Nat. Med. |volume=10 |issue=4 |pages=402–5 |date=April 2004 |pmid=15034571 |doi=10.1038/nm1021}}</ref><ref name="pmid14769355">{{cite journal |author=Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G |title=The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury |journal=Exp. Neurol. |volume=184 |issue=2 |pages=636–47 |date=December 2003 |pmid=14769355 |doi=10.1016/S0014-4886(03)00343-1 |url=http://linkinghub.elsevier.com/retrieve/pii/S0014488603003431}}</ref><ref name="pmid12057766">{{cite journal |author=Rakonczay Z, Iványi B, Varga I, ''et al.'' |title=Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats |journal=Free Radic. Biol. Med. |volume=32 |issue=12 |pages=1283–92 |date=June 2002 |pmid=12057766 |doi= 10.1016/S0891-5849(02)00833-X|url=http://linkinghub.elsevier.com/retrieve/pii/S089158490200833X}}</ref><ref>{{cite journal |author=Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L |title=Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats |journal=Exp. Neurol. |volume=176 |issue=1 |pages=87–97 |date=July 2002 |pmid=12093085 |doi= 10.1006/exnr.2002.7945|url=http://linkinghub.elsevier.com/retrieve/pii/S0014488602979458}}</ref><ref>{{cite journal |author=Benn SC, Brown RH |title=Putting the heat on ALS |journal=Nat. Med. |volume=10 |issue=4 |pages=345–7 |date=April 2004 |pmid=15057226 |doi=10.1038/nm0404-345}}</ref> It is believed to act at [[Hsp70]].<ref name="pmid17656567">{{cite journal |author=Brown IR |title=Heat shock proteins and protection of the nervous system |journal=Ann. N. Y. Acad. Sci. |volume=1113 |issue= |pages=147–58 |date=October 2007 |pmid=17656567 |doi=10.1196/annals.1391.032 |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2007&volume=1113&spage=147}}</ref> |
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== History == |
== History == |
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Arimoclomol has been shown to extend life in an animal model of ALS<ref name="pmid18673445">{{cite journal |author=Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L |title=Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS |journal=J. Neurochem. |volume=107 |issue=2 |pages=339–50 | |
Arimoclomol has been shown to extend life in an animal model of ALS<ref name="pmid18673445">{{cite journal |author=Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L |title=Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS |journal=J. Neurochem. |volume=107 |issue=2 |pages=339–50 |date=October 2008 |pmid=18673445 |doi=10.1111/j.1471-4159.2008.05595.x}}</ref> and was well tolerated in healthy human volunteers in a [[clinical trial#Phase I|Phase I]] study. CytRx is currently conducting a Phase II clinical trial.<ref name="urlPhase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov">{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT00706147 |title=Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov |format= |work= |accessdate=2009-05-18| archiveurl= http://web.archive.org/web/20090511060810/http://clinicaltrials.gov/ct2/show/NCT00706147| archivedate= 11 May 2009 <!--DASHBot-->| deadurl= no}}</ref> |
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Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat [[insulin resistance]]<ref>{{cite journal |author=Kürthy M, Mogyorósi T, Nagy K, ''et al.'' |title=Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models |journal=Ann. N. Y. Acad. Sci. |volume=967 |issue= |pages=482–9 | |
Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat [[insulin resistance]]<ref>{{cite journal |author=Kürthy M, Mogyorósi T, Nagy K, ''et al.'' |title=Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models |journal=Ann. N. Y. Acad. Sci. |volume=967 |issue= |pages=482–9 |date=June 2002 |pmid=12079878 |doi= 10.1111/j.1749-6632.2002.tb04306.x|url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2002&volume=967&spage=482}}</ref><ref>{{cite journal |author=Seböková E, Kürthy M, Mogyorosi T, ''et al.'' |title=Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance |journal=Ann. N. Y. Acad. Sci. |volume=967 |issue= |pages=424–30 |date=June 2002 |pmid=12079870 |doi= 10.1111/j.1749-6632.2002.tb04298.x|url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2002&volume=967&spage=424}}</ref> and diabetic complications such as [[diabetic retinopathy|retinopathy]], [[diabetic neuropathy|neuropathy]] and [[diabetic nephropathy|nephropathy]]. Later, the compound, along with other small molecules, was screened for further development by Hungarian firm Biorex, which was sold to CytRx Corporation, who developed it toward a different direction from 2003. |
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==References== |
==References== |
Revision as of 11:48, 14 January 2014
{{Drugbox | Watchedfields = changed | verifiedrevid = 443648965 | IUPAC_name = N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide | image = Arimoclomol.svg
| tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = Investigational | routes_of_administration = Oral
| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =
| CAS_number = 289893-25-0 | ATC_prefix = none | ATC_suffix = | PubChem = 208924 | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = 21106260 | UNII_Ref = | UNII = EUT3557RT5
| C=14 | H=20 | Cl=1 | N=3 | O=3 | molecular_weight = 313.78 g/mol | smiles = O[C@H](CN1CCCCC1)CO\N=C(\Cl)c2ccc[n+]([O-])c2 | InChI = 1/C14H20ClN3O3/c15-14(12-5-4-8-18(20)9-12)16-21-11-13(19)10-17-6-2-1-3-7-17/h4-5,8-9,13,19H,1-3,6-7,10-11H2/b16-14+/t13-/m1/s1 | InChIKey = SGEIEGAXKLMUIZ-ZPTIMJQQBD | StdInChI_Ref = | StdInChI = 1S/C14H20ClN3O3/c15-14(12-5-4-8-18(20)9-12)16-21-11-13(19)10-17-6-2-1-3-7-17/h4-5,8-9,13,19H,1-3,6-7,10-11H2/b16-14+/t13-/m1/s1 | StdInChIKey_Ref = | StdInChIKey = SGEIEGAXKLMUIZ-ZPTIMJQQSA-N }} Arimoclomol (INN, originally codenamed BRX-220) is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. The orally administered drug is intended to treat amyotrophic lateral sclerosis (ALS).[1][2]
Mechanism of action
Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases.
Arimoclomol activates the heat shock response.[3][4][5][6][7][8] It is believed to act at Hsp70.[9]
History
Arimoclomol has been shown to extend life in an animal model of ALS[10] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[11]
Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[12][13] and diabetic complications such as retinopathy, neuropathy and nephropathy. Later, the compound, along with other small molecules, was screened for further development by Hungarian firm Biorex, which was sold to CytRx Corporation, who developed it toward a different direction from 2003.
References
- ^ Cudkowicz ME, Shefner JM, Simpson E; et al. (July 2008). "Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis". Muscle Nerve. 38 (1): 837–44. doi:10.1002/mus.21059. PMID 18551622.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Traynor BJ, Bruijn L, Conwit R; et al. (July 2006). "Neuroprotective agents for clinical trials in ALS: a systematic assessment". Neurology. 67 (1): 20–7. doi:10.1212/01.wnl.0000223353.34006.54. PMID 16832072.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Kalmar B, Greensmith L (2009). "Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects". Cell. Mol. Biol. Lett. 14 (2): 319–35. doi:10.2478/s11658-009-0002-8. PMID 19183864.
- ^ Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L (April 2004). "Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice". Nat. Med. 10 (4): 402–5. doi:10.1038/nm1021. PMID 15034571.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G (December 2003). "The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury". Exp. Neurol. 184 (2): 636–47. doi:10.1016/S0014-4886(03)00343-1. PMID 14769355.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Rakonczay Z, Iványi B, Varga I; et al. (June 2002). "Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats". Free Radic. Biol. Med. 32 (12): 1283–92. doi:10.1016/S0891-5849(02)00833-X. PMID 12057766.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L (July 2002). "Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats". Exp. Neurol. 176 (1): 87–97. doi:10.1006/exnr.2002.7945. PMID 12093085.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Benn SC, Brown RH (April 2004). "Putting the heat on ALS". Nat. Med. 10 (4): 345–7. doi:10.1038/nm0404-345. PMID 15057226.
- ^ Brown IR (October 2007). "Heat shock proteins and protection of the nervous system". Ann. N. Y. Acad. Sci. 1113: 147–58. doi:10.1196/annals.1391.032. PMID 17656567.
- ^ Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L (October 2008). "Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS". J. Neurochem. 107 (2): 339–50. doi:10.1111/j.1471-4159.2008.05595.x. PMID 18673445.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ "Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov". Archived from the original on 11 May 2009. Retrieved 2009-05-18.
{{cite web}}
: Unknown parameter|deadurl=
ignored (|url-status=
suggested) (help) - ^ Kürthy M, Mogyorósi T, Nagy K; et al. (June 2002). "Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models". Ann. N. Y. Acad. Sci. 967: 482–9. doi:10.1111/j.1749-6632.2002.tb04306.x. PMID 12079878.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Seböková E, Kürthy M, Mogyorosi T; et al. (June 2002). "Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance". Ann. N. Y. Acad. Sci. 967: 424–30. doi:10.1111/j.1749-6632.2002.tb04298.x. PMID 12079870.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link)