P38 MAPK Inhibitor
BIRB 796
BIRB 796 (doramapimod) belongs to the diaryl urea class of inhibitors, binding to the allosteric site of human p38 mitogen activated protein kinase (MAPK). It can be used to study the regulation of proinflammatory cytokines, showing properties at nanomolar concentrations in cell cultures by suppressing the TNF-α production. The compound shows anti-inflammatory properties at nanomolar concentrations in cell cultures.
More information
p38 MAPK plays a crucial role in regulating the production of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1. Blocking this kinase may represent an interesting concept for treating inflammatory diseases. Doramapimod is a Boehringer Ingelheim frontrunner compound of the diaryl urea class of inhibitors, which binds to an allosteric site of human p38 MAP kinase. The formation of this binding site requires a large conformational change not observed previously for other kinases, occurring in the Asp-Phe-Gly motif within the active site. Requirement for this change in conformation are slow binding kinetics, which could be demonstrated in solution studies of the compound.
BIRB 796 in complex with p38 MAP kinase (PDB Code: 1KV2)
BIRB 796 inhibits the isoforms α-δ of p38 MAPK with IC50 values of 38-520 nM.
| PROBE NAME / NEGATIVE CONTROL | BIRB 796 |
| MW [Da, free base]a | 527.7 |
| p38α (IC50) [nM] | 38 |
| p38β (IC50) [nM] | 65 |
| p38γ (IC50) [nM] | 200 |
| p38δ (IC50) [nM] | 520 |
| B-Raf (IC50) [nM] | 83.4 |
a For the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
7 Assay conditions found in the reference 2
| PROBE NAME / NEGATIVE CONTROL | BIRB 796 |
| logP @ pH 11 | 4.30 |
| Solubility @ pH 6.8 [µg/mL] | <1 |
| Caco-2 permeability AB @ pH7.4 [*10-6 cm/s] | 33 |
| Caco-2 efflux ratio | 1.27 |
| MDCK permeability PappAB @ 1µM [10-6 cm/s] | 16 |
| MDCK efflux ratio | 1.88 |
| Microsomal stability (human/mouse/rat) [% QH] | 88 / 82 / >88 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 55 / - / 20 |
| Plasma Protein Binding (human/mouse/rat) [%] | 99.9 / >99.96 / >99.8 |
| hERG [inh. % @ 0.1 µM] | 14.8 |
| CYP 3A4 (IC50) [µM] | >50 |
| CYP 2C8 (IC50) [µM] | 1.4 |
| CYP 2C9 (IC50) [µM] | 5.0 |
| CYP 2C19 (IC50) [µM] | 8.9 |
| CYP 2D6 (IC50) [µM] | >10 |
| CYP 1A2 (IC50) [µM] | >10 |
DMPK parameters were shared in the reference2.
| BIRB 796 | MOUSE | RAT |
| Clearance [% QH] a | 0.33 [ml/min/kg] | 4 |
| tmax [h] b | 1.0 | n/A |
| Cmax [ng/mL] b | 27,000 | 5,500 |
| F [%] b | 23 | 75 |
| Vss [L/kg] a | 0.07 | 0.2 |
a i.v. dose: 1 mg/kg
b p.o. dose: 10 mg/kg
The ability of BIRB 796 to inhibit production of TNFa was tested in rat by suppression of local edema after carrageenan injection into the paw6. Additionally, the efficacy could be shown in humans by dose dependant reduction of cytokine production after oral administration8.
The SafetyScreen44™ panel has been measured (@10 mM) for BIRB 796, and for 0/44 proteins >70% inhibition was found. Highest inhibition was found for NA+/SITE2/R (65%), 5HT2AH_AGON (60%) and COX-2@CE (55%), respectively. Although it was found that BIRB 796 binds JNK2 in the nanomolar range, comparable to the p38 isoforms, the inhibition of the downstream pathway of JNK2 only occurs after treatment with micromolar doses.
| SELECTIVITY DATA AVILABLE | BIRB 796 |
SafetyScreen44™ with kind support of  | Yes |
| Invitrogen® | Yes |
| DiscoverX® | Yes |
| Dundee | No |
Download selectivity data:
BIRB-796_selectivityData.xlsx
The X-ray crystal structure of target in complex with BIRB 796 is available (PDB Code: 1KV2)1.
Other p38 MAPK inhibitors have been described in the literature2,3.
Doramapimod (BIRB 796) is an orally available, nanomolar inhibitor of p38 MAP kinase, showing a high selectivity compared to other proteins. It is a potent inhibitor of the p38 mitogen activated protein kinase (MAPK). The compound shows anti-inflammatory properties at nanomolar concentrations in cell cultures, which are based on the suppression of TNF-α production. Efficacy of the compound was also shown in animal models of endotoxin-stimulated TNF-α release and collagen-induced arthritis.
Pyrazole Urea-Based Inhibitors of p38 MAP Kinase: From Lead Compound to Clinical Candidate
Regan J., Breitfelder S., Cirillo P., Gilmore T., Graham A. G., Hickey E., Klaus B., Madwed J., Moriak M., Moss N., Pargellis C., Pav S., Proto A., Swinamer A., Tong L., Torcellini C.
J. Med. Chem. 2002, 45(14), 1994-3008.
Structure-Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)
Regan J., Capolino A., Cirillo P. F., Gilmore T., Graham A. G., Hickey E., Kroe R. R., Madwed J., Moriak M., Nelson R., Pargellis C. A., Swinamer A., Torcellini C., Tsang M, Moss N.
J. Med. Chem. 2003, 46(22), 4676-4686.
Inhibition of pro-inflammatory cytokine production by the dual p38/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling
Gruenbaum L. M., Schwartz R., Woska Jr J. R., DeLeon R. P., Peet G. W., Warren T. C., Capolino A., Mara L., Morelock M. M., Shrutkowski A., Jones J. W., Pargellis C. A.
Biochem. Pharmacol. 2009, 77(3), 422-432.
KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase
Montalban A. G., Boman E., Chang C-D., Ceide S. C., Dahl R., Dalesandro D., Delaet N. G. J., Erb E., Ernst J., Gibbs A., Kahl J., Kessler L., Lundström J., Miller S., Nakanishi H., Roberts E., Saiah E., Sullivan R., Wang Z., Larson C. J.
Eur. J. Pharmacol. 2010, 632, 93-102.
Anti-Inflammatory Effects of a p38 Mitogen-Activated Protein Kinase Inhibitor During Human Endotoxemia
Branger J., van den Blink B., Weijer S., Madwed J., Bos C. L., Gupta A., Yong C-L., Polmar S. H., Olszyna D. P., Hack C. E., van Deventer S. J. H., Peppelenbosch M. P., van der Poll T.
J. Immunol. 2002, 168(8), 4070-4077.
When you plan a publication, please use the following acknowledgement:
BIRB 796 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.