Tìm theo
Miglustat
Các tên gọi khác (10 ) :
  • BuDNJ
  • Butyldeoxynojirimycin
  • Miglustatum
  • N-(N-Butyl)deoxynojirimycin
  • N-Butyl deoxynojirimycin
  • N-Butyl-1-deoxynojirimycin
  • N-Butylmoranoline
  • NB-dnj
  • SC-48334
  • Zavesca
enzyme inhibitors
Thuốc Gốc
Small Molecule
CAS: 72599-27-0
ATC: A16AX06
ĐG : Actelion Pharmaceuticals Inc. , http://www.actelion.com
CTHH: C10H21NO4
PTK: 219.278
Miglustat is a drug used to treat Gaucher disease. It inhibits the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids. It is only used for patients who cannot be treated with enzyme replacement therapy with imiglucerase. Miglustat is marketed under the trade name Zavesca. Miglustat is now the first and only approved therapy for patients with Niemann-Pick disease type C (NP-C). It has recently been approved for treatment of progressive neurological symptoms in adult and pediatric patients in the European Union, Brazil, and South Korea. Miglustat was first developed as an anti-HIV agent in the 1990s. However, clinical experience with miglustat showed that therapeutic levels of the drug could not be achieved in patients without a high incidence of adverse effect.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C10H21NO4
Phân tử khối
219.278
Monoisotopic mass
219.147058165
InChI
InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9-,10-/m1/s1
InChI Key
InChIKey=UQRORFVVSGFNRO-UTINFBMNSA-N
IUPAC Name
(2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
Traditional IUPAC Name
miglustat
SMILES
CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Độ tan chảy
169-172 °C
Độ hòa tan
Highly soluble in water (>1000 mg/mL as a free base).
logP
-0.6
logS
0.18
pKa (strongest acidic)
12.9
pKa (Strongest Basic)
8.49
PSA
84.16 Å2
Refractivity
55.74 m3·mol-1
Polarizability
23.99 Å3
Rotatable Bond Count
4
H Bond Acceptor Count
5
H Bond Donor Count
4
Physiological Charge
1
Number of Rings
1
Bioavailability
1
Rule of Five
true
Dược Lực Học : Miglustat, an N-alkylated imino sugar, is a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for catalyzing the formation of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate for the endogenous glucocerebrosidase, an enzyme that is deficient in Gaucher's disease. The accumulation of glucosylceramide due to the absence of glucocerebrosidase results in the storage of this material in the lysosomes of tissue macrophages, leading to widespread pathology due to infiltration of lipid-engorged macrophages in the viscera, lymph nodes, and bone marrow. This results in secondary hematologic consequences including sever anemia and thrombocytopenia, in addition to the characteristic progressive hepatosplenomegaly, as well as skeletal complications including osteonecrosis and osteopenia with secondary pathological fractures.
Cơ Chế Tác Dụng : Miglustat is a drug used to treat Gaucher disease. It inhibits the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids. It is only used for patients who cannot be treated with enzyme replacement therapy with imiglucerase. Miglustat is marketed under the trade name Zavesca. Miglustat is now the first and only approved therapy for patients with Niemann-Pick disease type C (NP-C). It has recently been approved for treatment of progressive neurological symptoms in adult and pediatric patients in the European Union, Brazil, and South Korea. Miglustat was first developed as an anti-HIV agent in the 1990s. However, clinical experience with miglustat showed that therapeutic levels of the drug could not be achieved in patients without a high incidence of adverse effect. Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. The goal of treatment with miglustat is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy), reducing the accumulation of glucocerebroside in macrophages. In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. In clinical trials, miglustat improved liver and spleen volume, as well as hemoglobin concentration and platelet count. Inhibition of glycosphingolipid synthesis has also shown to reduce intracellular lipid storage, improve fluid-phase endosomal uptake and normalize lipid transport in peripheral blood B lymphocytes of NP-C patients, which results in a decrease in the potentially neurotoxic accumulation of gnagliosides GM2 and GM3, lactosylceramide and glucosylceramide, possibly preventing further neuronal damage. Other studies have also suggested that miglustat may indirectly modulate intracellular calcium homeostasis through its effects on glucosylceramide levels, and evidence has shown that an initiating factor in the pathogenesis of NP-C may be impaired calcium homeostasis related to sphingosine storage. Therefore, the effect that miglustat exerts on intracellular calcium levels may influence an important underlying pathogenic mechanism of NP-C.
Dược Động Học :
▧ Absorption :
Mean oral bioavailability is 97%.
▧ Protein binding :
Miglustat does not bind to plasma proteins.
▧ Metabolism :
There is no evidence that miglustat is metabolized in humans.
▧ Half Life :
The effective half-life of miglustat is approximately 6 to 7 hours.
Độc Tính : Miglustat has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.
Chỉ Định : For the treatment of adult patients with mild to moderate type 1 (nonneuropathic) Gaucher's disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access). Now approved in some countries for the treatment of progressive neurological symptoms in adult and pediatric patients with Niemann-Pick disease type C (NP-C).
Liều Lượng & Cách Dùng : Capsule - Oral
Dữ Kiện Thương Mại
Giá thị trường
  • Biệt dược thương mại : Zavesca 100 mg capsule
    Giá bán buôn : USD >160.67
    Đơn vị tính : capsule
Nhà Sản Xuất
Đóng gói
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB00419
PubChem Compound
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=51634
PubChem Substance
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46506350
ChemSpider
http://www.chemspider.com/Chemical-Structure.46764.html
BindingDB
http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=18355
PharmGKB
http://www.pharmgkb.org/drug/PA10140
Wikipedia
http://en.wikipedia.org/wiki/Miglustat
RxList
http://www.rxlist.com/cgi/generic3/zavesca.htm
Drugs.com
http://www.drugs.com/cdi/miglustat.html
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