1. Tetrahydroindazoles as Interleukin-2InducibleT-Cell Kinase Inhibitors. Part II. Second-Generation Analogueswith Enhanced Potency, Selectivity, and Pharmacodynamic Modulationin Vivo.
- Author
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JasonD. Burch, Kathy Barrett, Yuan Chen, Jason DeVoss, Charles Eigenbrot, Richard Goldsmith, M. Hicham A. Ismaili, Kevin Lau, Zhonghua Lin, Daniel F. Ortwine, Ali A. Zarrin, Paul A. McEwan, John J. Barker, Claire Ellebrandt, Daniel Kordt, Daniel B. Stein, Xiaolu Wang, Yong Chen, Baihua Hu, and Xiaofeng Xu
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INDAZOLES , *INTERLEUKIN-2 , *T cells , *KINASE inhibitors , *PHARMACODYNAMICS , *CELLULAR signal transduction - Abstract
The medicinal chemistry communityhas directed considerable effortstoward the discovery of selective inhibitors of interleukin-2 inducibleT-cell kinase (ITK), given its role in T-cell signaling downstreamof the T-cell receptor (TCR) and the implications of this target forinflammatory disorders such as asthma. We have previously discloseda structure- and property-guided lead optimization effort which resultedin the discovery of a new series of tetrahydroindazole-containingselective ITK inhibitors. Herein we disclose further optimizationof this series that resulted in further potency improvements, reducedoff-target receptor binding liabilities, and reduced cytotoxicity.Specifically, we have identified a correlation between the basicityof solubilizing elements in the ITK inhibitors and off-target antiproliferativeeffects, which was exploited to reduce cytotoxicity while maintainingkinase selectivity. Optimized analogues were shown to reduce IL-2and IL-13 production in vivo following oral or intraperitoneal dosingin mice. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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