posted on 2006-06-29, 00:00authored byVincent 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
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.