Chemistry:Arimoclomol

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Short description: Experimental drug
Arimoclomol
Arimoclomol.svg
Clinical data
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC14H20ClN3O3
Molar mass313.78 g·mol−1
3D model (JSmol)
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Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. In 2011 the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.[1] The European Medicines Agency (EMA) and U.S. Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.[2][3]

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.[4][5][6][7][8][9] It is believed to act at Hsp70.[10]

History

Arimoclomol has been shown to extend life in an animal model of ALS[11] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[12]

Arimoclomol also has been shown to be an effective treatment in an animal model of Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy's Disease).[13]

Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[14][15] 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

  1. ↑ "CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M | GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business | GEN". 17 May 2011. http://www.genengnews.com/gen-news-highlights/cytrx-sells-molecular-chaperone-assets-to-orphazyme-in-deal-worth/81245156?kwrd=Gleevec. 
  2. ↑ "European Medicines Agency - - EU/3/14/1376". http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b. 
  3. ↑ "Search Orphan Drug Designations and Approvals". https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814. 
  4. ↑ "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. 2009. doi:10.2478/s11658-009-0002-8. PMID 19183864. 
  5. ↑ "Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice". Nat. Med. 10 (4): 402–5. April 2004. doi:10.1038/nm1021. PMID 15034571. 
  6. ↑ "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. December 2003. doi:10.1016/S0014-4886(03)00343-1. PMID 14769355. 
  7. ↑ "Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats". Free Radic. Biol. Med. 32 (12): 1283–92. June 2002. doi:10.1016/S0891-5849(02)00833-X. PMID 12057766. 
  8. ↑ "Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats". Exp. Neurol. 176 (1): 87–97. July 2002. doi:10.1006/exnr.2002.7945. PMID 12093085. 
  9. ↑ "Putting the heat on ALS". Nat. Med. 10 (4): 345–7. April 2004. doi:10.1038/nm0404-345. PMID 15057226. 
  10. ↑ Brown IR (October 2007). "Heat shock proteins and protection of the nervous system". Ann. N. Y. Acad. Sci. 1113 (1): 147–58. doi:10.1196/annals.1391.032. PMID 17656567. Bibcode: 2007NYASA1113..147B. 
  11. ↑ "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. October 2008. doi:10.1111/j.1471-4159.2008.05595.x. PMID 18673445. 
  12. ↑ "Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov". http://clinicaltrials.gov/ct2/show/NCT00706147. 
  13. ↑ "Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy". Brain 136 (3): 926–943. 2013. doi:10.1093/brain/aws343. PMID 23393146. 
  14. ↑ "Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models". Ann. N. Y. Acad. Sci. 967 (1): 482–9. June 2002. doi:10.1111/j.1749-6632.2002.tb04306.x. PMID 12079878. Bibcode: 2002NYASA.967..482K. 
  15. ↑ "Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance". Ann. N. Y. Acad. Sci. 967 (1): 424–30. June 2002. doi:10.1111/j.1749-6632.2002.tb04298.x. PMID 12079870. Bibcode: 2002NYASA.967..424S. 



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