The non-diaryl heterocycle classes of p38 MAP kinase inhibitors.
The p38 mitogen activated protein (MAP) kinase is an integral enzyme involved in the production of a wide variety of pro-inflammatory cytokines from various cell types. The identification of this kinase and of the diaryl imidazole containing inhibitor, SB203580, initiated an intense discovery effort in this field. Numerous inhibitors were subsequently produced containing replacements for the imidazole, as well as some of the pharmacophores attached to it. During this time many other classes of potent p38 inhibitors emerged containing scaffolds and binding components not found in the diaryl imidazole group. This review summarizes nine of those classes. At least one of these classes requires the kinase to undergo reorganization prior to binding. From this diverse set of inhibitors four compounds have been reported advancing into human clinical trials.
Cirillo
Pier F
PF
Departments of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Research and Development Center, 900 Ridgebury Road, Ridgefield, CT 06877, USA. pcirillo@rdg.boehringer-ingelheim.com
Pargellis
Christopher
C
Regan
John
J
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004987:Ethers / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D004987:Ethers; D006571:Heterocyclic Compounds; D007659:Ketones; D014508:Urea; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases