p38 MAP kinase inhibitors: many are made, but few are chosen.
The mitogen-activated protein kinase (MAPK) p38 is a Ser/Thr kinase, originally isolated from lipopolysaccharide-stimulated monocytes. There are four isoforms of the enzyme (p38alpha, p38beta, p38gamma and p38delta), which differ in tissue distribution, regulation of kinase activation and subsequent phosphorylation of downstream substrates. These enzymes also differ in sensitivity to p38 MAPK inhibitors. The most thoroughly studied isoform is p38alpha, for which activation has been observed in many hematopoietic and non-hematopoietic cell types upon appropriate stimuli. p38alpha kinase is involved in the biosynthesis of the cytokines tumor necrosis factor-alpha and interleukin-1beta at the translational and transcriptional level. MAPK p38alpha represents a point of convergence for multiple signaling processes that are activated during inflammation, making it a key potential target for the modulation of cytokine production. The discovery and publication of p38alpha and a pyridinyl-imidazole-based p38alpha inhibitor initiated a huge effort by many companies to develop p38alpha inhibitors as potential treatments for inflammatory diseases. Herein, a brief overview is provided of the discovery and development of AMG-548 (Amgen Inc), a selective and efficacious p38alpha inhibitor, and its pharmacodynamic effects in a first-in-human study. Data from a phase I multidose clinical trial are also included. In addition, other p38alpha inhibitors that have advanced to clinical trials over the last three years are discussed, such as BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), SCIO-469 and SCIO-323 (Scios Inc), and VX-702 (Vertex Pharmaceuticals Inc/Kissei Pharmaceutical Co).
Dominguez
Celia
C
Amgen Inc, Chemistry Research & Discovery, Medicinal Chemistry, One Amgen Center Drive, MS 29-1-B, Thousand Oaks, CA 91320-179, USA. celiad@amgen.com
Powers
David A
DA
Tamayo
Nuria
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008958:Models, Molecular; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007211:Indoles; C499748:SCIO-469; D048051:p38 Mitogen-Activated Protein Kinases