Journal of Medicinal Chemistry 2006-06-29

Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma.

Vincent Pomel, Jasna Klicic, David Covini, Dennis D Church, Jeffrey P Shaw, Karen Roulin, Fabienne Burgat-Charvillon, Delphine Valognes, Montserrat Camps, Christian Chabert, Corinne Gillieron, Bernard Françon, Dominique Perrin, Didier Leroy, Denise Gretener, Anthony Nichols, Pierre Alain Vitte, Susanna Carboni, Christian Rommel, Matthias K Schwarz, Thomas Rückle

Index: J. Med. Chem. 49 , 3857-3871, (2006)

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Abstract

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.