Discovery of Novel PI3-Kinase 未 Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

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• 作者：Brian S. Safina ; Stewart Baker ; Matt Baumgardner ; Paul M. Blaney ; Bryan K. Chan ; Yung-Hsiang Chen ; Matthew W. Cartwright ; Georgette Castanedo ; Christine Chabot ; Arnaud J. Cheguillaume ; Paul Goldsmith ; David M. Goldstein ; Bindu Goyal ; Timothy Hancox ; Raj K. Handa ; Pravin S Iyer ; Jasmit Kaur ; Rama Kondru ; Jane R. Kenny ; Sussie L. Krintel ; Jun Li ; John Lesnick ; Matthew C. Lucas ; Cristina Lewis ; Sophie Mukadam ; Jeremy Murray ; Alan J. Nadin ; Jim Nonomiya ; Fernando Padilla ; Wylie S. Palmer ; Jodie Pang ; Neil Pegg ; Steve Price ; Karin Reif ; Laurent Salphati ; Pascal A. Savy ; Eileen M. Seward ; Stephen Shuttleworth ; Sukhjit Sohal ; Zachary K. Sweeney ; Suzanne Tay ; Parcharee Tivitmahaisoon ; Bohdan Waszkowycz ; Binqing Wei ; Qin Yue ; Chenghong Zhang ; Daniel P. Sutherlin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 28, 2012
• 年：2012
• 卷：55
• 期：12
• 页码：5887-5900
• 全文大小：570K
• 年卷期：v.55,no.12(June 28, 2012)
• ISSN：1520-4804

文摘

PI3K未 is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(伪, 尾, 未) and IB (纬), which catalyze the phosphorylation of PIP2 to PIP3. PI3K未 is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K未 inhibitors and describe a structural hypothesis for isoform (伪, 尾, 纬) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.