[(1S)-3-methyl-1-[(2R)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butyl]boronic acid

• ChemBase ID: 73
• Molecular Formular: C19H25BN4O4
• Molecular Mass: 384.2372
• Monoisotopic Mass: 384.1968857
• SMILES: O=C(N[C@H](CC(C)C)B(O)O)[C@H](NC(=O)c1nccnc1)Cc1ccccc1
• Canonical SMILES: CC(C[C@H](B(O)O)NC(=O)[C@H](NC(=O)c1cnccn1)Cc1ccccc1)C
• 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-/m1/s1
• InChIKey: GXJABQQUPOEUTA-NVXWUHKLSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: [(1S)-3-methyl-1-[(2R)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butyl]boronic acid
• IUPAC Traditional name: bortezomib
• Brand Name: Velcade
• Synonyms: bortezomib; Bortezomib

Database IDs

• CAS Number: 179324-69-7
• PubChem SID: 160963536
• PubChem CID: 93860

CALCULATED PROPERTIES

JChem

• Acid pKa: 13.037311
• H Acceptors: 6
• H Donor: 4
• LogD (pH = 5.5): 1.5302998
• LogD (pH = 7.4): 1.5302991
• Log P: 1.5303
• Molar Refractivity: 99.3738 cm^3
• Polarizability: 40.15836 Å^3
• Polar Surface Area: 124.44 Å^2
• Rotatable Bonds: 9
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 0.89
• LOG S: -3.86
• Solubility (Water): 5.32e-02 g/l

PROPERTIES

Physical Property

• Solubility: 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.

DETAILS

DrugBank - DB00188

• Drug Groups: approved; investigational
• Description: 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.
• Indication: For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.
• Pharmacology: 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.
• Toxicity: 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/m^2 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.
• Affected Organisms: Humans and other mammals
• Biotransformation: 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.
• 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.
• Protein Binding: 83% over the concentration range of 100-1000 ng/ml.
• Elimination: The pathways of elimination of bortezomib have not been characterized in humans.
• 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]
• References: Adams J, Kauffman M: Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004;22(2):304-11. [Pubmed] ; Bonvini P, Zorzi E, Basso G, Rosolen A: Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma. Leukemia. 2007 Apr;21(4):838-42. Epub 2007 Feb 1. [Pubmed] ; Voorhees PM, Dees EC, O'Neil B, Orlowski RZ: The proteasome as a target for cancer therapy. Clin Cancer Res. 2003 Dec 15;9(17):6316-25. [Pubmed] ; Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

REFERENCES

• Adams J, Kauffman M: Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004;22(2):304-11. Pubmed
• Bonvini P, Zorzi E, Basso G, Rosolen A: Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma. Leukemia. 2007 Apr;21(4):838-42. Epub 2007 Feb 1. Pubmed
• Voorhees PM, Dees EC, O'Neil B, Orlowski RZ: The proteasome as a target for cancer therapy. Clin Cancer Res. 2003 Dec 15;9(17):6316-25. Pubmed
• Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. Pubmed