Tìm theo
Bortezomib
Các tên gọi khác (4 ) :
  • N-[(1R)-1-(DIHYDROXYBORYL)-3-methylbutyl]-N-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide
  • PS 341
  • PS-341
  • Velcade
Thuốc Gốc
Small Molecule
CAS: 179324-69-7
ATC: L01XX32
ĐG : Ben Venue Laboratories Inc. , http://www.benvenue.com
CTHH: C19H25BN4O4
PTK: 384.237
Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C19H25BN4O4
Phân tử khối
384.237
Monoisotopic mass
384.196885774
InChI
InChI=1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
InChI Key
InChIKey=GXJABQQUPOEUTA-RDJZCZTQSA-N
IUPAC Name
[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butyl]boronic acid
Traditional IUPAC Name
(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butylboronic acid
SMILES
CC(C)C[[email protected]](NC(=O)[[email protected]](CC1=CC=CC=C1)NC(=O)C1=CN=CC=N1)B(O)O
Độ hòa tan
The solubility of bortezomib, as the monomeric boronic acid, is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.
logP
1.53
logS
-3.9
pKa (strongest acidic)
13.04
pKa (Strongest Basic)
-0.7
PSA
124.44 Å2
Refractivity
99.37 m3·mol-1
Polarizability
40.48 Å3
Rotatable Bond Count
9
H Bond Acceptor Count
6
H Bond Donor Count
4
Physiological Charge
0
Number of Rings
2
Bioavailability
1
Rule of Five
true
Ghose Filter
true
Dược Lực Học : Bortezomib is a drug that inhibits the mammalian 26S proteasome. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Tumor cells, that is, rapidly dividing cells, appear to be more sensitive to proteasome inhibition.
Cơ Chế Tác Dụng : Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease. Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Bortezomib is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).
Dược Động Học :

▧ Protein binding :
83% over the concentration range of 100-1000 ng/ml.
▧ Metabolism :
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2, while bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites which are inactive as 26S proteasome inhibitors.
▧ Route of Elimination :
The pathways of elimination of bortezomib have not been characterized in humans.
▧ Half Life :
The mean elimination half-life of bortezomib after first dose ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced malignancies.
▧ Clearance :
* 102 L/h [patients with multiple myeloma following the first dose for doses of 1 mg/m2] * 112 L/h [patients with multiple myeloma following the first dose for doses of 1.3 mg/m2] * 15 - 32 L/h [patients with multiple myeloma following subsequent doses for doses of 1 and 1.3 mg/m2]
Độc Tính : Cardiovascular safety pharmacology studies in monkeys show that lethal IV doses are associated with decreases in blood pressure, increases in heart rate, increases in contractility, and ultimately terminal hypotension. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in progressive hypotension starting at 1 hour and progressing to death by 12 to 14 hours following drug administration.
Chỉ Định : For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.
Tương Tác Thuốc :
  • Clopidogrel Moderate CYP2C19 Inhibitors like bortezomib may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Avoid concurrent use of moderate CYP2C19 inhibitors with clopidogrel whenever possible. If such a combination must be used, monitor closely for evidence of reduced clinical response to clopidogrel.
  • Etravirine Bortezombib, when used concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to avoid this combination.
  • Telithromycin Telithromycin may reduce clearance of Bortezomib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Bortezomib if Telithromycin is initiated, discontinued or dose changed.
  • Ticlopidine Ticlopidine may decrease the metabolism and clearance of Bortezomib. Consider alternate therapy or monitor for adverse/toxic effects of Bortezomib if Ticlopidine is initiated, discontinued or dose changed.
  • Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bortezomib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bortezomib if voriconazole is initiated, discontinued or dose changed.
Liều Lượng & Cách Dùng : Powder, for solution - Intravenous
Dữ Kiện Thương Mại
Giá thị trường
  • Biệt dược thương mại : Velcade 3.5 mg vial
    Giá bán buôn : USD >1590.0
    Đơn vị tính : vial
Nhà Sản Xuất
  • Công ty :
    Sản phẩm biệt dược : Velcade
... loading
... loading