Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

详细信息    查看全文

• 作者：Montse Erra ; Joan Taltavull ; Angelique Gréco ; Francisco Javier Bernal ; Juan Francisco Caturla ; Jordi Gràcia ; María Domínguez ; Mar Sabaté ; Stéphane Paris ; Salomé Soria ; Begoña Hernández ; Clara Armengol ; Judit Cabedo ; Mónica Bravo ; Elena Calama ; Montserrat Miralpeix ; Martin D. Lehner
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：118-123
• 全文大小：471K
• ISSN：1948-5875

文摘

The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure–activity relationships and structure–property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.