Spleen Tyrosine Kinase (SYK) is a promising target for the treatment of autoantibody-mediated diseases such as RA and SLE. Here we present a new and promising scaffold for orally available SYK inhibitors. SYK is a non-receptor tyrosine kinase. It mediates FcR (FcgRI, II, III, FceRI, FcaR) and BCR signaling. These mechanisms are involved in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Few SYK inhibitors are in clinical testing, however, they have some safety issues. Therefore, there is a strong need to develop safe and selective SYK inhibitors.We designed a target specific library of 50 novel compounds and screened it during a HTS campaign. One of the first hits showed a good potency of 390 nM (compound I). By rational drug design we could improve the potency to 20 nM. However, this compound inhibited 19 % of tested kinases with an IC50 < 1 �M. By specific structural changes, the KDR and SRC selectivity could be improved, leading to compounds like no II, which was 21 or 76 fold more active on SYK than on KDR and SRC, respectively. The overall kinase selectivity was 10 % (IC50< 1 �M, 168 kinases tested). Mouse PK parameters were unfavourable with an in vivo clearance of 3.8 L/h/kg and bioavailability of 14%, respectively. During the next optimization cycle, we identified compound III with 10 nM SYK potency, favourable selectivity (5 % of the kinases with an IC50 < 1 �M), including KDR and SRC. This compound is soluble (935 �g/ml) and has favourable PK profile in mice (Clearance 1.5 L/h/kg, bioavailability of 45 %). After oral administration in mice, compound III showed dose dependent efficacy in the ERK phosphorylation assay and Passive Cutaneous Anaphylaxis model, respectively. Furthermore, the compound showed inhibition of disease parameters in the mouse Collagen-Antibody Induced Arthritis model.

Furopyridines, discovery of a novel, potent, and selective class of spleen tyrosine kinase inhibitors with in vivo efficacy in a mouse collagen antibody-induced arthritis model

246th National Meeting (2013)

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