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Synthesis and Biological Testing of N ‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors
Author(s) -
Bracht Claudia,
Hauser Dominik R. J.,
Schattel Verena,
Albrecht Wolfgang,
Laufer Stefan A.
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000114
Subject(s) - p38 mitogen activated protein kinases , protein kinase a , kinase , chemistry , mitogen activated protein kinase , biochemistry , biology , pharmacology
The p38 mitogen‐activated protein (MAP) kinase α plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro‐inflammatory cytokines. To date, diverse p38α inhibitors are in phase II clinical trials for numerous cytokine‐dependent diseases. 2‐Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB 203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5‐tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region II (HR II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N ‐aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38α MAPK inhibitors.