285983-48-4 Usage
Description
Doramapimod is a potent and selective inhibitor of p38 mitogen-activated protein kinase (MAPK), belonging to the class of pyrazoles. It is an immunomodulator with anti-inflammatory activity, used for the treatment of various inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Doramapimod exhibits its effects by simultaneously binding to the ATP-binding domain and an allosteric site of p38 MAPK, leading to enhanced cytotoxicity and caspase activation.
Uses
1. Used in Pharmaceutical Industry:
Doramapimod is used as an immunomodulator for the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. It helps in modulating the immune response and reducing inflammation.
2. Used in Inflammatory Disease Treatment:
Doramapimod is used as an anti-inflammatory agent, blocking the upregulation of p38 MAPK and Hsp27 phosphorylation, which contributes to enhanced cytotoxicity and caspase activation in inflammatory conditions.
3. Used in Research and Development:
Doramapimod is used as a research tool for studying the role of p38 MAPK in various cellular processes and its potential as a therapeutic target for inflammatory diseases.
Chemical Properties:
Doramapimod is a pale beige solid with potent and selective inhibitory activity against p38 MAPK.
in vitro
birb 796 is a picomolar inhibitor of human p38 map kinase with a 12,000-fold increase in binding affinity. moreover, birb 796 behavors as one of the most potent and slowest dissociating human p38 map kinase inhibitors now known [1].
in vivo
in a lps-stimulated tnf-α synthesis mouse model, a 65% inhibition of tnf-α synthesis was observed when birb 796 was dosed orally at 10 mg/kg. in a model of established collagen-induced arthritis using b10.riii mice, birb 796 showed a 63% inhibition of arthritis severity when dosed orally at 30 mg/kg qd [2].
References
1) Pargellis?et al. (2002),?Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site; Nat. Struct. Biol.,?9?268
2) Branger?et al.?(2002),?Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia; J. Immunol.,?168?4070
3) Joos?et al. (2010),?Differential effects of p38MAP kinase inhibitors on the expression of inflammation-associated genes in primary, interleukin-1 beta-stimulated human chondrocytes; Br. J. Pharmacol.,?160?1252
Check Digit Verification of cas no
The CAS Registry Mumber 285983-48-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,8,5,9,8 and 3 respectively; the second part has 2 digits, 4 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 285983-48:
(8*2)+(7*8)+(6*5)+(5*9)+(4*8)+(3*3)+(2*4)+(1*8)=204
204 % 10 = 4
So 285983-48-4 is a valid CAS Registry Number.
InChI:InChI=1/C31H37N5O3/c1-22-9-11-23(12-10-22)36-29(21-28(34-36)31(2,3)4)33-30(37)32-26-13-14-27(25-8-6-5-7-24(25)26)39-20-17-35-15-18-38-19-16-35/h5-14,21H,15-20H2,1-4H3,(H2,32,33,37)
285983-48-4Relevant articles and documents
2,3-DIHYDRO-1H-INDENE-2-YL UREA DERIVATIVE AND PHARMACEUTICAL APPLICATION OF SAME
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Page/Page column 37, (2012/07/28)
A 2,3-dihydro-1H-indene-2-yl urea derivative represented by Formula (Ia) or a pharmaceutically acceptable salt thereof:
Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors
Simard, Jeffrey R.,Getlik, Matthaeus,Gruetter, Christian,Pawar, Vijaykumar,Wulfert, Sabine,Rabiller, Matthias,Rauh, Daniel
supporting information; experimental part, p. 13286 - 13296 (2010/01/30)
Kinase disregulation disrupts the intricate network of intracellular signaling pathways and contributes to the onset of diseases such as cancer. Although several kinase inhibitors are on the market, inhibitor selectivity and drug resistance mutations persist as fundamental challenges in the development of effective long-term treatments. Chemical entities binding to less conserved allosteric sites would be expected to offer new opportunities for scaffold development. Because no high-throughput method was previously available, we developed a fluorescence-based kinase binding assay for identifying and characterizing ligands which stabilize the inactive kinase conformation. Here, we present a description of the development and validation of this assay using the serine/threonine kinase p38R. By covalently attaching fluorophores to the activation loop of the kinase, we were able to detect conformational changes and measure the Kd, kon, and koff associated with the binding and dissociation of ligands to the allosteric pocket. We report the SAR of a synthesized focused library of pyrazolourea derivatives, a scaffold known to bind with high affinity to the allosteric pocket of p38R. Additionally, we used protein X-ray crystallography together with our assay to examine the binding and dissociation kinetics to characterize potent quinazoline- and quinoline-based type II inhibitors, which also utilize this binding pocket in p38α. Last, we identified the b-Raf inhibitor sorafenib as a potent low nanomolar inhibitor of p38α and used protein X-ray crystallography to confirm a unique binding mode to the inactive kinase conformation.
Synthesis of deuterium, tritium, and carbon-14 labeled BIRB 796, a p38 MAP kinase inhibitor
Latli, Bachir
, p. 847 - 856 (2007/10/03)
1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1-yl]urea (BIRB 796), currently in clinical trials for the treatment of inflammatory diseases, is a potent inhibitor of p38 MAP kinase. Labeled BIRB 796 with stable and r
