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BIRB 796 _Molecular_structure_CAS_285983-48-4)
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BIRB 796

Catalog No. S1574 Name Selleck Chemicals
CAS Number 285983-48-4 Website http://www.selleckchem.com
M. F. C31H37N5O3 Telephone (877) 796-6397
M. W. 527.65718 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 2748

SYNONYMS

IUPAC name
3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-{4-[2-(morpholin-4-yl)ethoxy]naphthalen-1-yl}urea
IUPAC Traditional name
doramapimod

DATABASE IDS

CAS Number 285983-48-4

PROPERTIES

Target p38 MAPK
Salt Data Free Base
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description Inflammation
Biological Activity
Description BIRB 796 (Doramapimod) is a highly selective p38α MAPK inhibitor to TNF-α with EC50 of 18 nM.
Targets TNF-α
IC50 18 nM (EC50) [1]
In Vitro BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2β, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-α, PKC-β (I and II) and PKC-γ. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. BIRB 796 represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known. [1] BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. [2] BIRB796 also inhibits the activity and the activation of SAPK3/p38γ at a higher concentration than it does in p38α. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. BIRB796 blocks JNK1/2 activation and activity in HEK293 cells, while not inhibits the activation and activity of ERK1/ERK2 in Hela cells. Moreover, the binding of BIRB796 to the p38 MAPKs or JNK1/2 is impairing their phosphorylation by the upstream kinase MKK6 or MKK4 rather than enhancing their dephosphorylation. [3] BIRB 796 blocks baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. BIRB 796 downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1. [4] BIRB-796 has a pyrazole scaffold that places a lipophilic t-butyl group into the lower selectivity site and a tolyl ring into the upper selectivity site. BIRB-796 also inhibits B-Raf and Abl with IC50 of 83?nM and 14.6?μM, respectively. [5]
In Vivo BIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis. [1] BIRB 796 has good pharmacokinetic performance even after oral administration in mice. [2]
Clinical Trials Boehringer Ingelheim has announced the discontinuation of BIRB 796 R&D project in 2005.
Features BIRB 796 is the first p38 MAPK inhibitor to reach phase III clinical trial.
Protocol
Kinase Assay [6]
Procedures for the THP-1 cellular assay for inhibition of LPS-stimulated TNF-α production THP-1 cells are preincubated in the presence and absence of BIRB 796 for 30 min. Cell mixture is stimulated with LPS (1 μg/mL final) and incubation continued overnight (18?24 hours) as above. Supernatant is analyzed for human TNF-α by a commercially available ELISA. Data are combined and analyzed by nonlinear regression using a three parameter logistic model to obtain an EC50 value. BIRB 796 is analyzed in each experiment and the 95% confidence intervals for the EC50 are between 16 and 22 nM.
Animal Study [2]
Animal Models Collagen-induced arthritis in female Balb/c mice
Formulation 70% PEG400 (intravenous) or 100% PEG400 (oral)
Doses 1 mg/kg (intravenous) or 10 mg/kg (oral)
Administration Intravenous injection or by oral
References
[1] Pargellis C, et al. Nat Struct Biol, 2002, 9(4), 268-272.
[2] Regan J, et al. J Med Chem, 2002, 45(14), 2994-3008.
[3] Kuma Y, et al. J Biol Chem, 2005, 280(20), 19472-19479.
[4] Yasui H, et al. Br J Haematol, 2007, 136(3), 414-423.
[5] Dietrich J, et al. Bioorg Med Chem. 2010, 18(15), 5738-5748.
[6] Regan J, et al. J Med Chem, 2003, 46(22), 4676-4686.