Identification of fused pyrimidines as interleukin 17 secretion inhibitors

Abstract

Inhibiting the interleukin 17 pathway is of interest in a number of autoimmune diseases. Herein, 42 fused pyrimidines have been evaluated as interleukin 17 secretion inhibitors using a phenotypic assay with peripheral blood mononuclear cells. 7H-Pyrrolo [2,3-d]pyrimidin-4-amines having aryl groups at C-5 or C-6 were found more active than the corresponding thieno- and furopyrimidines. Low cytotoxicity was seen for the most active inhibitors. However, the pyrrolopyrimidines also inhibit interleukin 5 secretion, suggesting that selective interleukin 17 inhibitors should rather be based on furopyrimidines. Profiling towards a panel of 51 kinases and assays towards the retinoic acid receptor-related orphan receptor gamma were performed in order to identify the compounds mode of action.

Keywords: Furopyrimidine; Interleukin 17 secretion; Interleukin 5; Pyrrolopyrimidine; Thienopyrimidine.