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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 386061800 |
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| verifiedrevid = 443493670 |
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| IUPAC_name = (3''R'',4''R'',5''R'')-3,4-Dihydroxy-5-(hydroxymethyl)piperidine <small>L</small>-(+)-tartrate |
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| IUPAC_name =(3''R'',4''R'',5''R'')-5-(Hydroxymethyl)-3,4-piperidinediol |
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| image = Isofagomine tartrate structure.svg |
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| image = Afegostat.svg |
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| CAS_number = 957230-65-8 |
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<!--Clinical data--> |
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| CAS_supplemental = |
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| tradename = Plicera |
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| ATC_prefix = none |
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| ATC_suffix = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| ATC_supplemental = |
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| pregnancy_category = |
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| PubChem = 23581846 |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| synonyms = AT-2101, HGT-3410 |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| chemical_formula = |
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| legal_status = Development terminated |
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| C=10 | H=19 | N=1 | O=9 |
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| molecular_weight = 297.25916 g/mol |
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| smiles = C1C(C(C(CN1)O)O)CO.C(C(C(=O)O)O)(C(=O)O)O |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category= |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = |
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| routes_of_administration = Oral |
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| routes_of_administration = Oral |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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<!--Identifiers--> |
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| IUPHAR_ligand = 7410 |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 169105-89-9 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = G23AP190YS |
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| ATC_prefix = none |
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| ATC_suffix = |
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| ATC_supplemental = |
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| ChEMBL = 206468 |
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| KEGG = D09576 |
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| PubChem = 447607 |
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| ChemSpiderID = 394649 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| synonyms = Isofagomine; AT-2101, HGT-3410 |
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<!--Chemical data--> |
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| chemical_formula = |
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| C=6 | H=13 | N=1 | O=3 |
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| smiles = C1(((CN1)O)O)CO |
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| StdInChI=1S/C6H13NO3/c8-3-4-1-7-2-5(9)6(4)10/h4-10H,1-3H2/t4-,5-,6-/m1/s1 |
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| StdInChIKey = QPYJXFZUIJOGNX-HSUXUTPPSA-N |
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}} |
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}} |
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'''Isofagomine tartrate''' (planned trade name '''Plicera''') is an experimental drug for the treatment of certain forms of ], developed by ] and ].<ref name="Spreitzer">{{cite journal |
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'''Afegostat''' (]; also known as '''isofagomine'''; planned trade name '''Plicera''') was an experimental drug for the treatment of certain forms of ] that was being developed by ] and ] until a failed clinical trial in 2009 led to termination of its development. The substance was used in form of the ]. |
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| author = H. Spreitzer |
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| date = 20 June 2009 |
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| title = Neue Wirkstoffe - Isofagomin tartrat |
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| journal = Österreichische Apothekerzeitung |
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| issue = 13/2009 |
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| pages = 736 |
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| language = German |
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}}</ref> |
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It has been granted ] status by the ] (EMA).<ref></ref> Isofagomine way invented ] and Troels Skrydstrup, and was first prepared by Jespersen and Bols.<ref>{{cite journal|last1=Jespersen|first1=T. M.|last2=Dong|first2=W|last3=Skrydstrup|first3=T|last4=Sierks|first4=M.R|last5=Lundt|first5=I|last6=Bols|first6=M.|title=Isofagomine, a Potent New Glycosidase Inhibitor|journal=Angew. Chem. Int. Ed. Engl.|year=1994|volume=33|issue=17|pages=1778–1779|doi=10.1002/anie.199417781}}</ref> |
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==Mechanism of action== |
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==Mechanism of action== |
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β-], an enzyme needed for the metabolisation of ], is misfolded in individuals with Gaucher's disease due to various mutations, one of which is called N370S. Isofagomine binds selectively to N370S glucocerebrosidase and restores its correct ] and, consequently, enhances its activity about threefold.<ref>{{cite journal |
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], an enzyme needed for the metabolisation of ], is misfolded in individuals with Gaucher's disease due to various mutations, one of which is called N370S. Afegostat, an ], binds selectively to N370S glucocerebrosidase and restores its correct ] and, consequently, enhances its activity about threefold.<ref>{{cite journal | vauthors = Dulsat C, Mealy N | title = Isofagomine tartrate | journal = Drugs of the Future | year = 2009 | volume = 34 | issue = 1 | pages = 23 | doi = 10.1358/dof.2009.034.01.1323946 | s2cid = 257862651 }}</ref><ref>{{cite journal | vauthors = Steet RA, Chung S, Wustman B, Powe A, Do H, Kornfeld SA | title = The iminosugar isofagomine increases the activity of N370S mutant acid beta-glucosidase in Gaucher fibroblasts by several mechanisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 37 | pages = 13813–8 | date = September 2006 | pmid = 16945909 | pmc = 1564243 | doi = 10.1073/pnas.0605928103 | bibcode = 2006PNAS..10313813S | doi-access = free }}</ref> |
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| author = Dulsat, C., Mealy, N. |
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| title = Isofagomine tartrate |
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| journal = Drugs of the Future |
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| year = 2009 |
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| volume = 34 |
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| issue = 1 |
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| pages = 23 |
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| url = http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1323946&p_IsPs=N |
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| doi = 10.1358/dof.2009.034.01.1323946 |
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}}</ref><ref>{{cite journal |
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| author = Richard A. Steet, Stephen Chung, Brandon Wustman, Allan Powe, Hung Do, and Stuart A. Kornfeld |
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| title = The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms |
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| journal = PNAS |
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| year = 2006 |
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| volume = 103 |
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| pages = 13813–8 |
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| url = http://www.pnas.org/content/103/37/13813.full.pdf+html?sid=9f370776-d7e1-4b29-b666-838676f51c76 |
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| doi = 10.1073/pnas.0605928103 |
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| pmid = 16945909 |
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| issue = 37 |
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| pmc = 1564243 |
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}}</ref> |
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==Invention and development== |
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==See also== |
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Afegostat was invented by ] and Troels Skrydstrup and was first prepared by Jespersen and Bols.<ref>{{cite journal| vauthors = Jespersen TM, Dong W, Sierks MR, Skrydstrup T, Lundt I, Bols M |title=Isofagomine, a Potent New Glycosidase Inhibitor |journal=Angewandte Chemie International Edition in English |year=1994 |volume=33 |issue=17 |pages=1778–1779|doi=10.1002/anie.199417781 }}</ref> |
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Amicus Therapeutics licensed patents related to afegostat from Mt. Sinai School of Medicine, University of Maryland, and ] A/S. They also signed a collaboration agreement with ] related to this drug and others.<ref name=AmiocusAR2010>{{cite web | author = Amicus Therapeutics, Inc. | url = http://ir.amicustherapeutics.com/secfiling.cfm?filingID=950123-10-23137&CIK=1178879 | title = Amicus 10-K Annual Report | date = 10 March 2010 |archive-url = https://web.archive.org/web/20160304032405/http://ir.amicustherapeutics.com/secfiling.cfm?filingID=950123-10-23137&CIK=1178879 |archive-date = 2016-03-04}}</ref>{{rp|13}} |
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It was granted ] status by the ] (EMA)<ref>{{cite web | url = http://www.emea.europa.eu/pdfs/human/comp/opinion/48831507en.pdf | title = Public summary of positive opinion for orphan designation of isofagomine tartrate for the treatment of Gaucher disease | archive-url = https://web.archive.org/web/20090718151103/http://www.emea.europa.eu/pdfs/human/comp/opinion/48831507en.pdf | archive-date = 18 July 2009 | publisher = European Medicines Agency | date = 10 March 2010 }}</ref> and by the ].<ref name=AmiocusAR2010/>{{rp|10}} |
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When afegostat failed a Phase II clinical trial in 2009, Shire terminated the collaboration agreement and Amicus determined it would no longer develop the afegostat.<ref name=AmiocusAR2010/>{{rp|2,10,11}} The first patents in Amicus' patent portfolio on afegostat expired in 2015.<ref name=AmiocusAR2010/>{{rp|12}} |
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== See also == |
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*], a recombinant human β-glucocerebrosidase for enzyme replacement therapy of Gaucher's disease |
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*], a recombinant human β-glucocerebrosidase for enzyme replacement therapy of Gaucher's disease |
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*], another orphan drug for the treatment of Gaucher's disease with a different mechanism of action |
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*], another orphan drug for the treatment of Gaucher's disease with a different mechanism of action |
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*] |
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==References== |
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== References == |
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{{Reflist}} |
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{{Reflist|2}} |
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{{pharma-stub}} |
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