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.

中文翻译：

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呋喃-2-基亚甲基噻唑烷二酮是磷酸肌醇3-激酶γ的新型，有效和选择性抑制剂。

I类磷酸肌醇3激酶（PI3K），尤其是PI3Kgamma，已成为炎性和自身免疫性疾病的诱人药物靶标。在这里，我们公开了一系列新的呋喃-2-基亚甲基噻唑烷二酮类化合物，它们是具有选择性的，ATP竞争性的PI3Kgamma抑制剂。由与PI3Kgamma结合的抑制剂形成的复合物的基于结构的设计和X射线晶体学确定了关键药效团特征的效力和选择性。分子的噻唑烷二酮部分上的酸性NH基和呋喃-2-基-苯基部分上的羟基在与PI3K结合中起关键作用，并有助于IB类PI3K选择性。通过这些努力，化合物26（AS-252424）是一种有效且选择性的小分子PI3Kgamma抑制剂，在三种不同的细胞PI3K分析中进一步分析了该蛋白，并显示出对IB类PI3K介导的细胞作用具有选择性。在急性腹膜炎的小鼠模型中口服给药26可显着减少白细胞募集。