Afegostat

Afegostat (INN; also known as isofagomine; planned trade name Plicera) was an experimental drug for the treatment of certain forms of Gaucher's disease that was being developed by Amicus Therapeutics and Shire plc until a failed clinical trial in 2009 led to termination of its development. The substance was used in form of the tartrate.

Afegostat
Clinical data
Trade namesPlicera
Other namesIsofagomine; AT-2101, HGT-3410
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Development terminated
Identifiers
IUPAC name
  • (3R,4R,5R)-5-(Hydroxymethyl)-3,4-piperidinediol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC6H13NO3
Molar mass147.174 g·mol−1
3D model (JSmol)
SMILES
  • C1[C@@H]([C@H]([C@@H](CN1)O)O)CO
InChI
  • InChI=1S/C6H13NO3/c8-3-4-1-7-2-5(9)6(4)10/h4-10H,1-3H2/t4-,5-,6-/m1/s1
  • Key:QPYJXFZUIJOGNX-HSUXUTPPSA-N
  (verify)

Mechanism of action

β-Glucocerebrosidase, an enzyme needed for the metabolisation of glucocerebroside, is misfolded in individuals with Gaucher's disease due to various mutations, one of which is called N370S. Afegostat, an iminosugar, binds selectively to N370S glucocerebrosidase and restores its correct conformation and, consequently, enhances its activity about threefold.[1][2]

Invention and development

Afegostat was invented by Mikael Bols and Troels Skrydstrup and was first prepared by Jespersen and Bols.[3]

Amicus Therapeutics licensed patents related to afegostat from Mt. Sinai School of Medicine, University of Maryland, and Novo Nordisk A/S. They also signed a collaboration agreement with Shire plc related to this drug and others.[4]: 13 

It was granted orphan drug status by the European Medicines Agency (EMA)[5] and by the US FDA.[4]: 10 

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.[4]: 2, 10, 11  The first patents in Amicus' patent portfolio on afegostat expired in 2015.[4]: 12 

See also
  • Imiglucerase, a recombinant human β-glucocerebrosidase for enzyme replacement therapy of Gaucher's disease
  • Miglustat, another orphan drug for the treatment of Gaucher's disease with a different mechanism of action
  • Eliglustat

References
  1. Dulsat C, Mealy N (2009). "Isofagomine tartrate". Drugs of the Future. 34 (1): 23. doi:10.1358/dof.2009.034.01.1323946.
  2. Steet RA, Chung S, Wustman B, Powe A, Do H, Kornfeld SA (September 2006). "The iminosugar isofagomine increases the activity of N370S mutant acid beta-glucosidase in Gaucher fibroblasts by several mechanisms". Proceedings of the National Academy of Sciences of the United States of America. 103 (37): 13813–8. Bibcode:2006PNAS..10313813S. doi:10.1073/pnas.0605928103. PMC 1564243. PMID 16945909.
  3. Jespersen TM, Dong W, Sierks MR, Skrydstrup T, Lundt I, Bols M (1994). "Isofagomine, a Potent New Glycosidase Inhibitor". Angewandte Chemie International Edition in English. 33 (17): 1778–1779. doi:10.1002/anie.199417781.
  4. Amicus Therapeutics, Inc. (10 March 2010). "Amicus 10-K Annual Report". Archived from the original on 2016-03-04.
  5. "Public summary of positive opinion for orphan designation of isofagomine tartrate for the treatment of Gaucher disease" (PDF). European Medicines Agency. 10 March 2010. Archived from the original (PDF) on 18 July 2009.
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