BMS561392 - CAS 611227-74-8
Catalog number: 611227-74-8
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C27H32N4O4
Molecular Weight:
476.57
COA:
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Targets:
TNF-alpha
Description:
BMS561392 is a tumor necrosis factor-alpha (TNF alpha) converting enzyme inhibitor. It has the potential treatment of diseases characterized by overproduction of TNF alpha, such as rheumatoid arthritis (RA). It was developed by Bristol-Myers Squibb and was in clinic phase 2 trials, but now it is terminated.
Purity:
98%
Appearance:
Solid powder
Synonyms:
BMS-561392; BMS561392; BMS 561392; DPC-333; DPC 333; DPC333. (αR,​3R)​-3-​Amino-​N-​hydroxy-​α-​(2-​methylpropyl)​-​3-​[4-​[(2-​methyl-​4-​quinolinyl)​methoxy]​phenyl]​-​2-​oxo-​1-​pyrrolidineacetamide​;BMS-561392;DPC-333;(2R)-2-[(3R)-3-amino-3-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]-2-oxopyrrolidin-1-yl]-N-hyd
Solubility:
Soluble in DMSO, not in water
Storage:
-20°C Freezer
MSDS:
Inquire
Application:
BMS561392 has the potential treatment of diseases characterized by overproduction of TNF alpha, such as rheumatoid arthritis (RA).
Quality Standard:
In-house standard
Quantity:
Milligrams-Grams
Density:
1.253±0.06 g/cm3 | Condition: Temp: 20 °C Press: 760 Torr
InChIKey:
QVNZBDLTUKCPGJ-SHQCIBLASA-N
InChI:
InChI=1S/C27H32N4O4/c1-17(2)14-24(25(32)30-34)31-13-12-27(28,26(31)33)20-8-10-21(11-9-20)35-16-19-15-18(3)29-23-7-5-4-6-22(19)23/h4-11,15,17,24,34H,12-14,16,28H2,1-3H3,(H,30,32)/t24-,27-/m1/s1
Canonical SMILES:
CC1=NC2=CC=CC=C2C(=C1)COC3=CC=C(C=C3)C4(CCN(C4=O)C(CC(C)C)C(=O)NO)N
Current Developer:
BMS561392 was developed by Bristol-Myers Squibb and was in clinic phase 2 trials, but now it is terminated.
1.Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia.
Jia HP;Look DC;Tan P;Shi L;Hickey M;Gakhar L;Chappell MC;Wohlford-Lenane C;McCray PB Jr Am J Physiol Lung Cell Mol Physiol. 2009 Jul;297(1):L84-96. doi: 10.1152/ajplung.00071.2009. Epub 2009 May 1.
Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase and the receptor for the SARS and NL63 coronaviruses (CoV). Loss of ACE2 function is implicated in severe acute respiratory syndrome (SARS) pathogenesis, but little is known about ACE2 biogenesis and activity in the airways. We report that ACE2 is shed from human airway epithelia, a site of SARS-CoV infection. The regulation of ACE2 release was investigated in polarized human airway epithelia. Constitutive generation of soluble ACE2 was inhibited by DPC 333, implicating a disintegrin and metalloprotease 17 (ADAM17). Phorbol ester, ionomycin, endotoxin, and IL-1beta and TNFalpha acutely induced ACE2 release, further supporting that ADAM17 and ADAM10 regulate ACE2 cleavage. Soluble ACE2 was enzymatically active and partially inhibited virus entry into target cells. We determined that the ACE2 cleavage site resides between amino acid 716 and the putative transmembrane domain starting at amino acid 741. To reveal structural determinants underlying ACE2 release, several mutant and chimeric ACE2 proteins were engineered. Neither the juxtamembrane stalk region, transmembrane domain, nor the cytosolic domain was needed for constitutive ACE2 release.
2.Effect of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a human tumor necrosis factor alpha-converting enzyme inhibitor, on the disposition of methotrexate: a transporter-based drug-drug interaction case study.
Luo G;Garner CE;Xiong H;Hu H;Richards LE;Brouwer KL;Duan J;Decicco CP;Maduskuie T;Shen H;Lee FW;Gan LS Drug Metab Dispos. 2007 Jun;35(6):835-40. Epub 2007 Mar 1.
DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.
3.Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis.
Moss ML;Sklair-Tavron L;Nudelman R Nat Clin Pract Rheumatol. 2008 Jun;4(6):300-9. doi: 10.1038/ncprheum0797. Epub 2008 Apr 15.
The success of agents that inhibit tumor necrosis factor (TNF), such as infliximab, adalimumab and etanercept, has led to a desire for orally available small molecules that have a better safety profile and are less costly to produce than current agents. One target for anti-TNF therapy that is currently under investigation is TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor. Inhibitors of this enzyme with drug-like properties have been made and tested in the clinic. These inhibitors include TMI-005 and BMS-561392, both of which have entered into phase II clinical trials. This article summarizes preclinical and clinical findings regarding the use of inhibitors of TNF-converting enzyme for the treatment of rheumatoid arthritis.
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