Potent and Highly Selective Benzimidazole Inhibitors of PI3-Kinase Delta

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• 作者：Jeremy M. Murray ; Zachary K. Sweeney ; Bryan K. Chan ; Mercedesz Balazs ; Erin Bradley ; Georgette Castanedo ; Christine Chabot ; David Chantry ; Michael Flagella ; David M. Goldstein ; Rama Kondru ; John Lesnick ; Jun Li ; Matthew C. Lucas ; Jim Nonomiya ; Jodie Pang ; Stephen Price ; Laurent Salphati ; Brian Safina ; Pascal P. A. Savy ; Eileen M. Seward ; Mark Ultsch ; Daniel P. Sutherlin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7686-7695
• 全文大小：502K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Inhibition of PI3K未 is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3K未. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3K未 inhibitors. Instead, the selectivity of the compounds for inhibition of PI3K未 relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3K未 binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.