Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase Inhibitors
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- 作者：Jason D. Burch ; Kevin Lau ; John J. Barker ; Fred Brookfield ; Yong Chen ; Yuan Chen ; Charles Eigenbrot ; Claire Ellebrandt ; M. Hicham A. Ismaili ; Adam Johnson ; Daniel Kordt ; Colin H. MacKinnon ; Paul A. McEwan ; Daniel F. Ortwine ; Daniel B. Stein ; Xiaolu Wang ; Dirk Winkler ; Po-Wai Yuen ; Yamin Zhang ; Ali A. Zarrin ; Zhonghua Pei
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：July 10, 2014
- 年：2014
- 卷：57
- 期：13
- 页码：5714-5727
- 全文大小：667K
- ISSN：1520-4804
文摘
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.