2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

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• 作者：Leena Patel ; Jayaraman Chandrasekhar ; Jerry Evarts ; Aaron C. Haran ; Carmen Ip ; Joshua A. Kaplan ; Musong Kim ; David Koditek ; Latesh Lad ; Eve-Irene Lepist ; Mary E. McGrath ; Nikolai Novikov ; Stephane Perreault ; Kamal D. Puri ; John R. Somoza ; Bart H. Steiner ; Kirk L. Stevens ; Joseph Therrien ; Jennifer Treiberg ; Armando G. Villaseñor ; Arthur Yeung ; Gary Phillips
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3532-3548
• 全文大小：767K
• 年卷期：0
• ISSN：1520-4804

文摘

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.