Design and Synthesis of 4-Azaindoles as Inhibitors of p38 MAP Kinase

Abstract

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.

Computational Sampling of a Cryptic Drug Binding Site in a Protein Receptor: Explicit Solvent Molecular Dynamics and Inhibitor Docking to p38 MAP Kinase

“…Two of the selected inhibitors, a simple diaryl urea inhibitor and BIRB796, bind crystallographically to the DFG-out conformation. 3,8 The remaining three ligands, a pyridinylimidazole inhibitor, 12 a dihydroquinazolinone inhibitor, 13 and a 4-azaindole inhibitor, 14 all bind crystallographically to the ATP binding pocket, with the DFG motif in its more usual DFG-in conformation.…”

Rationales Design von hoch aktiven und selektiven Liganden für α5β1‐ und αvβ3‐Integrine

“…Der Aminopyridylalkohol 1 wurde durch nucleophile aromatische Substitution aus dem kommerziell erhältlichen 2-Brompyridin und 3-Aminopropanol bei 150 8C in 95 % Ausbeute erhalten (Schema 1). [23] Die methylsubstituierten Aminopyridylalkohole wurden aus den jeweiligen 2-Chlormethylpyridinen durch Oxidation mit meta-Chlorperbenzoesäure zum N-Oxid (78-89 %), [24] nucleophile aromatische Substitution (> 95 %) und Reduktion unter H 2 -Atmosphäre mit einem Pd-Katalysator (60-82 %) erhalten (Schema 2). Die Aminopyridylalkohole wurden anschließend mit den Boc-geschützten a-oder b-Tyrosinmethylestern in einer Mitsunobu-Reaktion mit Tributylphosphin und Azodicarbonyldipiperidid (ADDP) umgesetzt.…”

Gold catalysis in the synthesis of azaindoles: pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrazines

“…On the other side, 5H-pyrrolo [2,3-b]pyrazines (or 4,7-diazaindoles) ( Figure 1) have recently gained attention since derivatives of the system exhibit diverse biological activities. In addition to showing antibronchospastic effects 11 and the ability to inhibit the activity of a mitogenactivated protein kinase (p38 MAP) 12 and a Janus kinase (JAK3), 13 some other derivatives can inhibit cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3 (GSK-3), thereby exerting antiproliferative effects. [14][15][16][17] Abnormalities and deregulations of CDK activities have been associated with many diseases, including cancer, viral infections, diabetes, ischemia and neurodegenerative disorders such as Alzheimer′s and Parkinson′s diseases.…”