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Maxim Masiutin (talk | contribs) Added the cs1 style template to denote Vancouver ("vanc") citation style, because references contain "vauthors" attribute to specify the list of authors. Added s2cid. | Use this tool. Report bugs. | #UCB_Gadget |
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{{Short description|Experimental drug}} |
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{{cs1 config|name-list-style=vanc}} |
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{{Drugbox |
{{Drugbox |
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| Verifiedfields = changed |
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| verifiedrevid = 447557873 |
| verifiedrevid = 447557873 |
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| IUPAC_name = N-{[(2''R'')-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide |
| IUPAC_name = N-<nowiki/>{[(2''R'')-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide |
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| image = Arimoclomol.svg |
| image = Arimoclomol.svg |
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| metabolism = |
| metabolism = |
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| elimination_half-life = |
| elimination_half-life = |
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| excretion = |
| excretion = |
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<!--Identifiers--> |
<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 289893-25-0 |
| CAS_number = 289893-25-0 |
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| ATC_prefix = |
| ATC_prefix = N07 |
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| ATC_suffix = |
| ATC_suffix = XX17 |
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| PubChem = 208924 |
| PubChem = 208924 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
| DrugBank = |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 2107726 |
| ChEMBL = 2107726 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = EUT3557RT5 |
| UNII = EUT3557RT5 |
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| KEGG = D11374 |
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<!--Chemical data--> |
<!--Chemical data--> |
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| C=14 | H=20 | Cl=1 | N=3 | O=3 |
| C=14 | H=20 | Cl=1 | N=3 | O=3 |
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| molecular_weight = 313.78 g/mol |
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| smiles = O[C@H](CN1CCCCC1)CO\N=C(\Cl)c2ccc[n+]([O-])c2 |
| smiles = O[C@H](CN1CCCCC1)CO\N=C(\Cl)c2ccc[n+]([O-])c2 |
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| 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 |
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| InChIKey = SGEIEGAXKLMUIZ-ZPTIMJQQBD |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| 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 |
| 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 |
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| StdInChIKey = SGEIEGAXKLMUIZ-ZPTIMJQQSA-N |
| StdInChIKey = SGEIEGAXKLMUIZ-ZPTIMJQQSA-N |
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}} |
}} |
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'''Arimoclomol''' ([[International Nonproprietary Name|INN]]; originally codenamed '''BRX-345''', which is a citrate salt formulation of '''BRX-220''') is an experimental drug developed by [[CytRx|CytRx Corporation]], a biopharmaceutical company based in [[Los Angeles, California]]. |
'''Arimoclomol''' ([[International Nonproprietary Name|INN]]; originally codenamed '''BRX-345''', which is a citrate salt formulation of '''BRX-220''') is an experimental drug developed by [[CytRx|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.<ref>{{cite web|title=CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M {{!}} GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business {{!}} GEN|url=http://www.genengnews.com/gen-news-highlights/cytrx-sells-molecular-chaperone-assets-to-orphazyme-in-deal-worth/81245156?kwrd=Gleevec|website=GEN|date = 17 May 2011}}</ref> 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.<ref>{{cite web|title=European Medicines Agency - - EU/3/14/1376|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b|website=www.ema.europa.eu|access-date=2022-02-15|archive-date=2017-07-28|archive-url=https://web.archive.org/web/20170728004205/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Forphans%2F2015%2F01%2Fhuman_orphan_001465.jsp&mid=WC0b01ac058001d12b|url-status=dead}}</ref><ref>{{cite web|title=Search Orphan Drug Designations and Approvals|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814|website=www.accessdata.fda.gov}}</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 | |
Arimoclomol activates the [[heat shock protein|heat shock]] response.<ref name="pmid19183864">{{cite journal |vauthors=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|pmc=6275696 }}</ref><ref name="pmid15034571">{{cite journal |vauthors=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|s2cid=2311751 }}</ref><ref name="pmid14769355">{{cite journal |vauthors=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 |s2cid=5316222 }}</ref><ref name="pmid12057766">{{cite journal |vauthors=Rakonczay Z, Iványi B, Varga I |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|display-authors=etal}}</ref><ref>{{cite journal |vauthors=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|s2cid=16071543 }}</ref><ref>{{cite journal |vauthors=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|s2cid=11434434 }}</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 |pages=147–58 |date=October 2007 |issue=1 |pmid=17656567 |doi=10.1196/annals.1391.032 |bibcode=2007NYASA1113..147B |s2cid=36782230 }}</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 | |
Arimoclomol has been shown to extend life in an animal model of ALS<ref name="pmid18673445">{{cite journal |vauthors=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|doi-access= |s2cid=30026592 }}</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 |access-date=2009-05-18| archive-url= https://web.archive.org/web/20090511060810/http://clinicaltrials.gov/ct2/show/NCT00706147| archive-date= 11 May 2009 | url-status= live}}</ref> |
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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). |
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).<ref name="pmid23393146">{{cite journal |vauthors=Malik B, Nirmalananthan N, Gray A, La Spada A, Hanna M, Greensmith L |title=Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy |journal=Brain |volume= 136|issue=3 |pages=926–943 |date=2013 |pmid=23393146 | url= |doi=10.1093/brain/aws343 |pmc=3624668}}</ref> |
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Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat [[insulin resistance]]<ref>{{cite journal | |
Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat [[insulin resistance]]<ref>{{cite journal |vauthors=Kürthy M, Mogyorósi T, Nagy K |title=Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models |journal=Ann. N. Y. Acad. Sci. |volume=967 |pages=482–9 |date=June 2002 |issue=1 |pmid=12079878 |doi= 10.1111/j.1749-6632.2002.tb04306.x|bibcode=2002NYASA.967..482K |s2cid=19585837 |display-authors=etal}}</ref><ref>{{cite journal |vauthors=Seböková E, Kürthy M, Mogyorosi T |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 |pages=424–30 |date=June 2002 |issue=1 |pmid=12079870 |doi= 10.1111/j.1749-6632.2002.tb04298.x|bibcode=2002NYASA.967..424S |s2cid=23338560 |display-authors=etal}}</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== |
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{{Other nervous system drugs}} |
{{Other nervous system drugs}} |
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[[Category:Drugs acting on the nervous system]] |
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[[Category:1-Piperidinyl compounds]] |
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[[Category:3-Pyridyl compounds]] |
Latest revision as of 20:46, 10 March 2024
Clinical data | |
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Routes of administration | Oral |
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ChEMBL | |
CompTox Dashboard (EPA) | |
Chemical and physical data | |
Formula | C14H20ClN3O3 |
Molar mass | 313.78 g·mol−1 |
3D model (JSmol) | |
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(what is this?) (verify) |
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
- ^ "CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M | GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business | GEN". GEN. 17 May 2011.
- ^ "European Medicines Agency - - EU/3/14/1376". www.ema.europa.eu. Archived from the original on 2017-07-28. Retrieved 2022-02-15.
- ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov.
- ^ 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. PMC 6275696. 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. S2CID 2311751.
- ^ 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. S2CID 5316222.
- ^ 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.
- ^ 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. S2CID 16071543.
- ^ Benn SC, Brown RH (April 2004). "Putting the heat on ALS". Nat. Med. 10 (4): 345–7. doi:10.1038/nm0404-345. PMID 15057226. S2CID 11434434.
- ^ Brown IR (October 2007). "Heat shock proteins and protection of the nervous system". Ann. N. Y. Acad. Sci. 1113 (1): 147–58. Bibcode:2007NYASA1113..147B. doi:10.1196/annals.1391.032. PMID 17656567. S2CID 36782230.
- ^ 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. S2CID 30026592.
- ^ "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.
- ^ Malik B, Nirmalananthan N, Gray A, La Spada A, Hanna M, Greensmith L (2013). "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. doi:10.1093/brain/aws343. PMC 3624668. PMID 23393146.
- ^ 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 (1): 482–9. Bibcode:2002NYASA.967..482K. doi:10.1111/j.1749-6632.2002.tb04306.x. PMID 12079878. S2CID 19585837.
- ^ 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 (1): 424–30. Bibcode:2002NYASA.967..424S. doi:10.1111/j.1749-6632.2002.tb04298.x. PMID 12079870. S2CID 23338560.