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

• ChemBase ID: 2748
• Molecular Formular: C31H37N5O3
• Molecular Mass: 527.65718
• Monoisotopic Mass: 527.28964007
• SMILES: Cc1ccc(cc1)n1nc(cc1NC(=O)Nc1ccc(OCCN2CCOCC2)c2c1cccc2)C(C)(C)C
• Canonical SMILES: O=C(Nc1cc(nn1c1ccc(cc1)C)C(C)(C)C)Nc1ccc(c2c1cccc2)OCCN1CCOCC1
• InChI: InChI=1S/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)
• InChIKey: MVCOAUNKQVWQHZ-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• 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
• Synonyms: 1-(5-Tert-Butyl-2-P-Tolyl-2h-Pyrazol-3-Yl)-3-[4-(2-Morpholin-4-Yl-Ethoxy)-Naphthalen-1-Yl]-Urea; BIRB 796

Database IDs

• CAS Number: 285983-48-4
• PubChem SID: 160966196; 46506062
• PubChem CID: 156422

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.464863
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 5.068174
• LogD (pH = 7.4): 6.276217
• Log P: 6.3700423
• Molar Refractivity: 157.0099 cm^3
• Polarizability: 60.95927 Å^3
• Polar Surface Area: 80.65 Å^2
• Rotatable Bonds: 8
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: 5.32
• LOG S: -5.15
• Solubility (Water): 3.75e-03 g/l

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: p38 MAPK

Product Information

• Salt Data: Free Base

DETAILS

DrugBank - DB03044

Drug information: experimental

Selleck Chemicals - S1574

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

• 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.
• Protocol: 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

• References: [1] Pargellis C, et al. Nat Struct Biol, 2002, 9(4), 268-272.
• References: [2] Regan J, et al. J Med Chem, 2002, 45(14), 2994-3008.
• References: [3] Kuma Y, et al. J Biol Chem, 2005, 280(20), 19472-19479.
• References: [4] Yasui H, et al. Br J Haematol, 2007, 136(3), 414-423.
• References: [5] Dietrich J, et al. Bioorg Med Chem. 2010, 18(15), 5738-5748.
• References: [6] Regan J, et al. J Med Chem, 2003, 46(22), 4676-4686.

REFERENCES

• Pargellis C, et al. Nat Struct Biol, 2002, 9(4), 268-272.
• Regan J, et al. J Med Chem, 2002, 45(14), 2994-3008.
• Kuma Y, et al. J Biol Chem, 2005, 280(20), 19472-19479.
• Yasui H, et al. Br J Haematol, 2007, 136(3), 414-423.
• Dietrich J, et al. Bioorg Med Chem. 2010, 18(15), 5738-5748.
• Regan J, et al. J Med Chem, 2003, 46(22), 4676-4686.