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Revision as of 04:03, 1 July 2011
{{drugbox | Verifiedfields = changed | UNII_Ref = | UNII = EUT3557RT5 | verifiedrevid = 399530982 | IUPAC_name = N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide | image = Arimoclomol.svg | ChemSpiderID_Ref = | ChemSpiderID = 21106260 | 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 | smiles = O[C@H](CN1CCCCC1)CO\N=C(\Cl)c2ccc[n+]([O-])c2 | 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 | CAS_number = 289893-25-0 | ATC_prefix = none | ATC_suffix = | PubChem = 208924 | DrugBank = | C=14|H=20|Cl=1|N=3|O=3 | molecular_weight = 313.78 g/mol | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | pregnancy_AU = | pregnancy_US = | pregnancy_category= | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = Investigational | routes_of_administration = Oral }} 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. (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}}
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Traynor BJ, Bruijn L, Conwit R; et al. (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.
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ignored (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 (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}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G (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.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rakonczay Z, Iványi B, Varga I; et al. (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.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L (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.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Benn SC, Brown RH (2004). "Putting the heat on ALS". Nat. Med. 10 (4): 345–7. doi:10.1038/nm0404-345. PMID 15057226.
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ignored (help) - ^ Brown IR (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.
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ignored (help) - ^ Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L (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.
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ignored (help)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". Retrieved 2009-05-18.
- ^ Kürthy M, Mogyorósi T, Nagy K; et al. (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.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Seböková E, Kürthy M, Mogyorosi T; et al. (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.
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ignored (help)CS1 maint: multiple names: authors list (link)