April 7, 2014
Treat immunological or inflammatory disorders with ITK inhibitors. F. Brookfield and co-inventors report pyrazole carboxamide derivatives (represented generally by formula 1) that inhibit interleukin-2-inducible T-cell kinase (ITK). The compounds may be developed as drugs for treating immunological or inflammatory disorders and other diseases that are responsive to ITK inhibition.
ITK belongs to the Tec family of kinases. It is expressed in T cells, natural killer cells, natural killer T cells, and mast cells. Activated ITK mediates T cell receptor (TCR) signals by phosphorylating and activating phospholipase C-g. Studies show that ITK knockout mice exhibit reduced lung inflammation, mucus production, and airway hyper-reactivity in allergic asthma models. The studies also show that the kinase activity of ITK is necessary for asthma pathology. In addition, ITK is expressed at high levels in peripheral blood T cells of humans who have immunological and inflammatory disorders such as atopic dermatitis.
ITK inhibition presents a viable therapeutic target for treating the immunological or inflammatory disorders mediated by this kinase. The inventors disclose the structures of 154 examples of formula 1 and many of their stereo- and structural isomers. The four representative compounds in the figure represent single enantiomers, but their absolute stereochemistry is not specified.
The inventors report the equilibrium dissociation constant (Ki) values for ITK inhibition by all described examples of formula 1. The Ki values ranged from <0.1 to 4000 nM, as illustrated by the selected examples 2–5 in the table.
(Genentech [San Francisco]. WIPO Publication 2014023258, Feb.13, 2014; Ahmed F. Abdel-Magid)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.