Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma
| Autor: | Corinne Gillieron, Christian Chabert, Thomas Rückle, Jasna Klicic, Denise Gretener, Jeffrey P. Shaw, Karen Roulin, Didier Leroy, Fabienne Burgat-Charvillon, Dennis D. Church, Susanna Carboni, Matthias Schwarz, Delphine Valognes, Pierre Alain Vitte, Anthony Nichols, Bernard Françon, Vincent Pomel, Dominique Perrin, David Covini, Montserrat Camps, Christian Rommel |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry medicine.drug_class Neutrophils Bone Marrow Cells Peritonitis Crystallography X-Ray Monocytes Mice Phosphatidylinositol 3-Kinases Structure-Activity Relationship Drug Discovery medicine Moiety Animals Class Ib Phosphatidylinositol 3-Kinase Humans Mast Cells Binding site Thiazolidinedione Phosphorylation Furans Cells Cultured Phosphoinositide-3 Kinase Inhibitors chemistry.chemical_classification Phosphoinositide 3-kinase biology Molecular Structure Chemotaxis Isoenzymes Enzyme Biochemistry chemistry Enzyme inhibitor Thioglycolates Acute Disease biology.protein Molecular Medicine Thiazolidinediones Pharmacophore Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of medicinal chemistry. 49(13) |
| ISSN: | 0022-2623 |
| Popis: | Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kgamma, have become attractive drug targets for inflammatory and autoimmune diseases. Here, we disclose a novel series of furan-2-ylmethylene thiazolidinediones as selective, ATP-competitive PI3Kgamma inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3Kgamma identified key pharmacophore features for potency and selectivity. An acidic NH group on the thiazolidinedione moiety and a hydroxy group on the furan-2-yl-phenyl part of the molecule play crucial roles in binding to PI3K and contribute to class IB PI3K selectivity. Compound 26 (AS-252424), a potent and selective small-molecule PI3Kgamma inhibitor emerging from these efforts, was further profiled in three different cellular PI3K assays and shown to be selective for class IB PI3K-mediated cellular effects. Oral administration of 26 in a mouse model of acute peritonitis led to a significant reduction of leukocyte recruitment. |
| Databáze: | OpenAIRE |
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