Discovery of Selective and Orally Bioavailable Protein Kinase C theta (PKC theta) Inhibitors from a Fragment Hit

作者：George Dawn M^*; Breinlinger Eric C; Friedman Michael; Zhang Yang; Wang Jianfei; Argiriadi Maria; Bansal Pakala Pratima; Barth Martine; Duignan David B; Honore Prisca; Lang QiugYu; Mittelstadt Scott; Potin Dominique; Rundell Lian; Edmunds Jeremy J

来源：Journal of Medicinal Chemistry, 2015, 58(1): 222-236.

DOI：10.1021/jm500669m

Protein kinase C theta (PKC theta) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKC theta inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.

• 出版日期2015-1-8