Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo

  • J Med Chem. 2015 May 14;58(9):3806-16. doi: 10.1021/jm501998m.
Jason D Burch  1 ,  Kathy Barrett  1 ,  Yuan Chen  1 ,  Jason DeVoss  1 ,  Charles Eigenbrot  1 ,  Richard Goldsmith  1 ,  M Hicham A Ismaili  1 ,  Kevin Lau  1 ,  Zhonghua Lin  1 ,  Daniel F Ortwine  1 ,  Ali A Zarrin  1 ,  Paul A McEwan  2 ,  John J Barker  2 ,  Claire Ellebrandt  3 ,  Daniel Kordt  3 ,  Daniel B Stein  3 ,  Xiaolu Wang  3 ,  Yong Chen  4 ,  Baihua Hu  4 ,  Xiaofeng Xu  4 ,  Po-Wai Yuen  4 ,  Yamin Zhang  4 ,  Zhonghua Pei  1
Affiliations
  • 1. †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. ‡Evotec (U.K.) Ltd., 114 Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
  • 3. §Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.
  • 4. ∥Pharmaron Beijing Ltd. Co., No. 6 TaiHe Road BDA, 100176 Beijing, P. R. China.
PMID: 25844760 DOI: 10.1021/jm501998m
Abstract

The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (Itk), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective Itk inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the Itk inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.

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