1557232-08-2Relevant academic research and scientific papers
Tetrahydroindazoles as interleukin-2 inducible T-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity, and pharmacodynamic modulation in vivo
Burch, Jason D.,Barrett, Kathy,Chen, Yuan,DeVoss, Jason,Eigenbrot, Charles,Goldsmith, Richard,Ismaili, M. Hicham A.,Lau, Kevin,Lin, Zhonghua,Ortwine, Daniel F.,Zarrin, Ali A.,McEwan, Paul A.,Barker, John J.,Ellebrandt, Claire,Kordt, Daniel,Stein, Daniel B.,Wang, Xiaolu,Chen, Yong,Hu, Baihua,Xu, Xiaofeng,Yuen, Po-Wai,Zhang, Yamin,Pei, Zhonghua
, p. 3806 - 3816 (2015/05/27)
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.
Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible t-cell kinase inhibitors
Burch, Jason D.,Lau, Kevin,Barker, John J.,Brookfield, Fred,Chen, Yong,Chen, Yuan,Eigenbrot, Charles,Ellebrandt, Claire,Ismaili, M. Hicham A.,Johnson, Adam,Kordt, Daniel,Mackinnon, Colin H.,McEwan, Paul A.,Ortwine, Daniel F.,Stein, Daniel B.,Wang, Xiaolu,Winkler, Dirk,Yuen, Po-Wai,Zhang, Yamin,Zarrin, Ali A.,Pei, Zhonghua
, p. 5714 - 5727 (2014/08/05)
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.
PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Page/Page column 130, (2014/03/21)
Provided herein are compounds of formula (AA): N N H HN O N N R R 6 A (R a ) p, (AA) stereoisomers or a pharmaceutically acceptable salt thereof, wherein A, R a, p, R and R 6 are defined herein, compositions including the compounds and methods of manufacturing and using the compounds for the treatment of diseases.
