Uses
TAK 715 is a p38 MAPK inhibitor for p38α and p38β but not for p38γ and p38δ.
Definition
ChEBI: N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide is a member of benzamides.
Biological Activity
tak-715 is a selective inhibitor of p38 mapk with ic50 value of 7.1 nm [1].p38 mitogen-activated protein (map) kinases (p38 mapks) are a class of mitogen-activated protein kinases and play an important role in controlling cellular responses to cytokines and stress. four p38 mapks contain members, p38-α (mapk14), p38-β (mapk11), p38-γ (mapk12/erk6), and p38-δ (mapk13/sapk4), have been identified. abnormal expression of p38 mapks are correlated with a variety of chronic inflammatory diseases and their inhibitors are regarded as promising targets in clinical [1] [2].tak-715 is a potent p38 mapk inhibitor and has a different selectivity with the reported p38 mapk inhibitor vx-745. when tested with human monocytic thp-1 cells, administration of tak-715 exhibited inhibition on p38mapkα with ic50 value of 7.1 nm [1]. in hek293t, u2os, and f9 cells, tak-715 was used to inhibit p38 mapk activity and concluded that p38 mapk had no function in wnt/β-catenin signaling pathway [2].in adjuvant-induced rheumatoid arthritis rat model, administration of tak-715 at dose of 10 mg/kg significantly decreased lps-induced stimulated release of tnf-α (87.6%) by inhibiting p38 mapk activity [1].
in vivo
TAK-715 (compound 8h; 3-30 mg/kg; PO) significantly reduces the secondary paw volume[1].
TAK-715 (10 mg/kg; PO) has a Cmax of 0.19 μg/mL and an AUC of 1.16 μg h/mL.
| Animal Model: | 7-week-old male Lewis rats with arthritis[1] |
| Dosage: | 3, 10, 30 mg/kg |
| Administration: | PO; single dose |
| Result: | Significantly reduced the secondary paw volume (25% inhibition)
|
| Animal Model: | Rat[1] |
| Dosage: | 10 mg/kg (Pharmacokinetic Analysis) |
| Administration: | PO |
| Result: | Had a Cmax of 0.19 μg/mL and an AUC of 1.16 μg?h/mL.
|
IC 50
p38α: 7.1 nM (IC50); p38β: 200 nM (IC50); p38δ: >10 μM (IC50); p38γ: >10 μM (IC50); CK1δ; CK1ε
References
[1]. miwatashi, s., et al., novel inhibitor of p38 map kinase as an anti-tnf-alpha drug: discovery of n-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (tak-715) as a potent and orally active anti-rheumatoid arthritis agent. j med chem, 2005. 48(19): p. 5966-79.
[2]. verkaar, f., et al., inhibition of wnt/beta-catenin signaling by p38 map kinase inhibitors is explained by cross-reactivity with casein kinase idelta/varepsilon. chem biol, 2011. 18(4): p. 485-94.
