Description
Miglustat is an N-alkylated iminosugar, launched as an oral treatment for mild to
moderate type 1 Gaucher’s disease in adult patients for whom enzyme replacement
therapy is not a therapeutic option. It is readily synthesized from D-glucose in three steps by first converting to N-butylglucamine via reductive amination with
butylamine, followed by a microbial oxidation to an aminofuranose intermediate
and subsequent reductive cyclization. Type 1 Gaucher’s disease is a metabolic
disorder caused by the lysosomal accumulation of certain glycosphingolipids (GSLs)
as a result of deficiency in their degradation. Enlargement of the liver and spleen,
low blood platelet and bone lesions are among the key symptoms of this disease.
Miglustat acts by inhibiting glucosylceramide synthase, a glucosyl transferase
enzyme in the biosynthesis of most GSLs, which results in the lowering of GSLs to
a level that can be effectively cleared. Up to 50% reduction in liver and splenocyte
GSL levels are achieved in mice by long-term administration of Miglustat (600–
1800 mg/kg/day for 118 days). Miglustat, dosed at 50 and 100 mg in Gaucher
patients, exhibits dose proportionate pharmacokinetics (tmax=2.5 h, t1/2=6 to 7 h)
and ＞90% oral bioavailability. Steady-state plasma levels are reached after 4–6
weeks of treatment. Miglustat is not significantly metabolized in humans and the
major route of excretion is renal. In clinical trials, efficacy was demonstrated by
significant reductions in liver and spleen volumes (12 and 19%, respectively) at 12
months and increase in hemoglobin and platelet count (0.91 g/dL and 13.6×109/l,
respectively) at 24 months. Miglustat is generally well tolerated by patients and the
most common side effects are diarrhea and weight loss.
Originator
G.D. Searle (Pfizer) (US)
Uses
Treatment of glycolipid storage diseases.
Definition
ChEBI: A hydroxypiperidine that is deoxynojirimycin in which the amino hydrogen is replaced by a butyl group.
Brand name
Zavesca(Actelion);Vevesca.
General Description
N-Butyldeoxynojirimycin is an alkylated product of imino sugar deoxynojirimycin.
Biological Activity
Orally active α -glucosidase I and II and ceramide-specific glycosyltransferase inhibitor. Rescues trafficking-deficient F508del-CTFR in human airway epithelial cells via inhibition of ER α -glucosidases I and II. Also has broad spectrum antiviral activity.
Biochem/physiol Actions
N-Butyldeoxynojirimycin is an inhibitor of glucosyltransferase and α-glucosidases. N-Butyldeoxynojirimycin, also known as misglustat, reduces glycolipid levels by substrate reduction therapy (SRT) and is effectively used for the treatment of glycosphingolipid lysosomal storage disorder, Gaucher disease.
