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

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

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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