<i>Tetra</i>-Substituted Pyridinylimidazoles
As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase
and c‑Jun <i>N</i>‑Terminal Kinase 3 for Potential
Treatment of Neurodegenerative Diseases
Felix Muth
Marcel Günther
Silke M. Bauer
Eva Döring
Sabine Fischer
Julia Maier
Peter Drückes
Jürgen Köppler
Jörg Trappe
Ulrich Rothbauer
Pierre Koch
Stefan A. Laufer
10.1021/jm501557a.s001
https://acs.figshare.com/articles/journal_contribution/_i_Tetra_i_Substituted_Pyridinylimidazoles_As_Dual_Inhibitors_of_p38_Mitogen_Activated_Protein_Kinase_and_c_Jun_i_N_i_Terminal_Kinase_3_for_Potential_Treatment_of_Neurodegenerative_Diseases/2218084
<i>Tetra</i>-substituted imidazoles were designed as
dual inhibitors of c-Jun <i>N</i>-terminal kinase (JNK)
3 and p38α mitogen-activated protein (MAP) kinase. A library
of 45 derivatives was prepared and evaluated in a kinase activity
assay for their ability to inhibit both kinases, JNK3 and p38α
MAP kinase. Dual inhibitors with IC<sub>50</sub> values down to the
low double-digit nanomolar range at both enzymes were identified.
The best balanced dual JNK3/p38α MAP kinase inhibitors are <b>6m</b> (IC<sub>50</sub>: JNK3, 18 nM; p38α, 30 nM) and <b>14d</b> (IC<sub>50</sub>: JNK3, 26 nM; p38α, 34 nM) featuring
both excellent solubility and metabolic stability. They may serve
as useful tool compounds for preclinical proof-of-principle studies
in order to validate the synergistic role of both kinases in the progression
of Huntington’s disease.
2015-01-08 00:00:00
p 38α MAP kinase
45 derivatives
Dual inhibitors
JNK 3
IC 50 values
Dual Inhibitors
nanomolar range
nM
Potential Treatment
tool compounds
kinase activity assay
6 m