Doramapimod

p38α

527.66

DMSO : 125 mg/mL (236.89 mM; Need ultrasonic)
Ethanol : 33.33 mg/mL (63.17 mM; Need ultrasonic)

White or off-white solid

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. BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC₅₀ of 1.4 and 0.1 nM, respectively. 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. 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. 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.

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. BIRB 796 has good pharmacokinetic performance even after oral administration in mice.

达马莫德

C₃₁H₃₇N₅O₃

285983-48-4