Furan-2-ylmethylene Thiazolidinediones as Novel, Potent, and Selective Inhibitors of Phosphoinositide 3-Kinase γ

• Published in: Journal of medicinal chemistry 2006-06, Vol.49 (13), p.3857-3871
• Main Authors: Pomel, Vincent, Klicic, Jasna, Covini, David, Church, Dennis D, Shaw, Jeffrey P, Roulin, Karen, Burgat-Charvillon, Fabienne, Valognes, Delphine, Camps, Montserrat, Chabert, Christian, Gillieron, Corinne, Françon, Bernard, Perrin, Dominique, Leroy, Didier, Gretener, Denise, Nichols, Anthony, Vitte, Pierre Alain, Carboni, Susanna, Rommel, Christian, Schwarz, Matthias K, Rückle, Thomas
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - physiology; Bones, joints and connective tissue. Antiinflammatory agents; Cells, Cultured; Chemotaxis - drug effects; Class Ib Phosphatidylinositol 3-Kinase; Crystallography, X-Ray; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Mast Cells - drug effects; Mast Cells - metabolism; Medical sciences; Mice; Models, Molecular; Molecular Structure; Monocytes - drug effects; Monocytes - physiology; Neutrophils - immunology; Peritonitis - chemically induced; Peritonitis - drug therapy; Peritonitis - immunology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - chemistry; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Structure-Activity Relationship; Thiazolidinediones - chemical synthesis; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology; Thioglycolates
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0601598

Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kγ, 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 PI3Kγ inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3Kγ 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 PI3Kγ 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.