Afegostat (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; also known as isofagomine; planned trade name Plicera) was an experimental drug for the treatment of certain forms of

Gaucher's disease Gaucher's disease or Gaucher disease () (GD) is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polyg ...

that was being developed by

Amicus Therapeutics Amicus Therapeutics is a public American biopharmaceutical company based in Philadelphia, PA. The company went public in 2007 under the NASDAQ trading symbol FOLD. This followed a 2006 planned offering and subsequent withdrawal, which would have ...

and

Shire plc Shire plc was a UK-founded Jersey-registered specialty biopharmaceutical company. Originating in the United Kingdom with an operational base in the United States, its brands and products included Vyvanse, Lialda, and Adderall XR. Shire was ac ...

until a failed clinical trial in 2009 led to termination of its development. The substance was used in form of the

tartrate A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−. The main forms of tartrates used commercially are pure crystalline ta ...

Mechanism of action

β-Glucocerebrosidase, an enzyme needed for the metabolisation of

glucocerebroside Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose. Clinical significance In Gaucher disease, the enzyme glucocerebrosidase is nonfunctional and cannot break down glucocer ...

, is misfolded in individuals with Gaucher's disease due to various mutations, one of which is called N370S. Afegostat, an

iminosugar An iminosugar, also known as an iminosaccharide, is any analog of a sugar where a nitrogen atom has replaced the oxygen atom in the ring of the structure. Iminosugars are common components of plants and may be responsible for some of their medicin ...

, binds selectively to N370S glucocerebrosidase and restores its correct conformation and, consequently, enhances its activity about threefold.

Invention and development

Afegostat was invented by

Mikael Bols Mikael Bols (born July 28, 1961) is a synthetic organic chemistry, organic chemist who is mainly known for his work on carbohydrates and artificial enzymes. Early life Mikael Bols was born and grew up in Copenhagen, Denmark. He attended high scho ...

and Troels Skrydstrup and was first prepared by Jespersen and Bols. Amicus Therapeutics licensed patents related to afegostat from Mt. Sinai School of Medicine, University of Maryland, and

Novo Nordisk Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...

A/S. They also signed a collaboration agreement with

related to this drug and others. It was granted

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) and by the

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

. 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. The first patents in Amicus' patent portfolio on afegostat expired in 2015.

References

{{Reflist, 2 Orphan drugs Piperidines

Mechanism of action

Invention and development

See also

References