Doramapimod (BIRB 796)

2 years -80 in solvent

Intravenous injection or by oral

Boehringer Ingelheim has announced the discontinuation of BIRB 796 R&D project in 2005.

70% PEG400 (intravenous) or 100% PEG400 (oral)

BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2beta, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-alpha, PKC-beta (I and II) and PKC-gamma. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38alpha. 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 Jnk2alpha2 with IC50 of 1.4 and 0.1 nM, respectively. [2] BIRB796 also inhibits the activity and the activation of SAPK3/p38gamma at a higher concentration than it does in p38alpha. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38gamma. 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-alpha and TGF-beta1. [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 uM, respectively. [5]

[6], Procedures for the THP-1 cellular assay for inhibition of LPS-stimulated TNF-alpha production, THP-1 cells are preincubated in the presence and absence of BIRB 796 for 30 min. Cell mixture is stimulated with LPS (1 ug/mL final) and incubation continued overnight (18 24 hours) as above. Supernatant is analyzed for human TNF-alpha 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.

Doramapimod (BIRB 796) is a pan-p38 MAPK inhibitor with IC50 of 38 nM, 65 nM, 200 nM and 520 nM for p38α/β/γ/δ in cell-free assays, and binds p38α with Kd of 0.1 nM in THP-1 cells, 330-fold greater selectivity versus JNK2, weak inhibition for c-RAF, Fyn and Lck, insignificant inhibition of ERK-1, SYK, IKK2.

BIRB 796 is the first p38 MAPK inhibitor to reach phase III clinical trial.