1557249-50-9Relevant articles and documents
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.
