Pyridinyl imidazoles

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

Lali, F. V., Hunt, A. E., Turner, S. J., and Foxwell, B. M. (2000). The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independendy ofp38 mitogen-activated protein kinase. J. Biol. Chem. 275, 7395-7402. 

Previous studies have reported that ERKs are characteristically associated with cell proliferation and protection from apoptosis (Bl, XI), while activation of JNK and p38 MAPK can promote apoptosis in many systems, including B lymphocytes (G5), cerebellar granule cells (K3), hematopoietic cells (K8), and neuronal cells (M3, XI). On the other hand, a recent report found that a pyridinyl imidazole, SB 202190, the specific inhibitor of p38 MAPK, by itself was sufficient to induce apoptosis in T lymphocyte Jurkat cells (N2). Moreover, Th-2-derived cytokine IL-5, the ERK activator and antiapoptotic factor for eosinophils, could also activate p38 MAPK in human eosinophils (BIO). We recently reported that cytokine IL-3, IL-5, and GM-CSF could prolong survival of human eosinophilic leukemic (EoL-1) cells through the transient activation of ERK (W15). On the other hand, activation of p38 MAPK in EoL-1 cells by the NSAID sodium salicylate (NaSal) could lead to apoptosis (W15). We also found that the suppression of ERK using ERK antisense phosphorothioate oligodeoxynucleotides could promote the apoptosis of peripheral blood eosinophils (W16). Moreover, we found that dexamethasone-induced apoptosis and activation of JNK and p38 MAPK activity in eosinophils are regulated by caspases (Z2). 

CH3im(CH3py) l-methyl-3-[2-(3-methyl)pyridinyl]imidazol-2-ylidene CH3im(CH2py) l-methyl-3-(2-pyridinylmethyl)imidazol-2-ylidene CH3impy l-methyl-3-(2-pyridinyl)imidazol-2-ylidene... 

Pyridinyl imidazoles have been used as fluorescent reporters of binding to p38a MAP kinase.12,13 To measure kon for test compounds, the kinase was... 

Ac-Imidazole, PtCl2(C2H4), 23°, 0.5-144 h, 51-87% yield. Platinum(II) acts as a template to catalyze the acetylation of the pyridinyl alcohol, C5H4N(CH2) CH20H. Normally acylimidazoles are not very reactive acy-lating agents with alcohols. 

D3, Ci]-l-[(6-Chloro-3-pyridinyl)methyl]-4,5-dihydro-1 //-imidazol-2-amine trifluoracetate... 

Hutzler, J.M., Steenwyk, R.C., Smith, E.B., Walker, G.S. and Wienkers, L.C. (2004) Mechanism-based inactivation of cytochrome P450 2D6 by l-[(2-ethyl-4-methyl-1 H-imidazol-5-yl) methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine kinetic characterization and evidence for apoprotein adduction. Chemical Research in Toxicology, 17 (2), 174—184. 

Omeprazole 5 -Methoxy-2- [(4 -methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinylj -17/-benzimidazol O-methylation, imidazole ring formation using thiourea, A-oxidation, nucleophilic displacement, A-methylation, S -oxidation... 

Chemical Name Guanidine, N-(3-(4-fluorophenyl)-3-(2-pyridinyl)propyl)-N -(3-(lH-imidazol-4-yl)propyl)-... 

Pd-catalyzed Cross-couplings with Boron and Tin. GlaxoSmithKline utilized PCys as an effective ligand in a Suzuki reaction to access a large amount of [4-(3-pyridinyl)-l//-imidazol-l-yl]acetaldehyde for the preparation of macrolide derivatives... 

Reactions of [Co(NH3)6] with pyridinyl carboxylate radicals, L, have been compared with reactions of the carboxylate-bound radical in [(NH3)5CoL f Only the species [(NH3)5Co02CCH20COC5H4N ] " decays by an intramolecular route with a first-order rate constant of 4 x 10 s , while radicals of quaternized pyridine derivatives are oxidized by [(NH3)5CoL] complexes in solution. The coordinated imidazole in [(NH3)5CoImH] traps an electron more rapidly than the cobalt(ni) center allowing detection of an intermediate in pulse-radiolysis experiments and the determination of the intramolecular electron transfer rate as 2.5 x 10 s . ... 

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