Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors

详细信息    查看全文

• 作者：Klemens Hoegenauer ; Nicolas Soldermann ; Frédéric Stauffer ; Pascal Furet ; Nadege Graveleau ; Alexander B. Smith ; Christina Hebach ; Gregory J. Hollingworth ; Ian Lewis ; Sascha Gutmann ; Gabriele Rummel ; Mark Knapp ; Romain M. Wolf ; Joachim Blanz ; Roland Feifel ; Christoph Burkhart ; Frédéric Zécri
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：7
• 期：8
• 页码：762-767
• 全文大小：404K
• 年卷期：0
• ISSN：1948-5875

文摘

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction–reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.