Discovery and Structure鈭扐ctivity Relationship of 3-Aminopyrid-2-ones as Potent and Selective Interleukin-2 Inducible T-Cell Kinase (Itk) Inhibitors

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• 作者：Jean-Damien Charrier ; Andrew Miller ; David P. Kay ; Guy Brenchley ; Heather C. Twin ; Philip N. Collier ; Sharn Ramaya ; Shazia B. Keily ; Steven J. Durrant ; Ronald M. A. Knegtel ; Adam J. Tanner ; Kieron Brown ; Adam P. Curnock ; Juan-Miguel Jimenez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2341-2350
• 全文大小：1080K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K_i of 7 nM and has a good selectivity profile across kinases.