R406, 14, is the active form of the phosphate prodrug R788, 15 [69,70]. Compound 14 has an IC50 of 41 nM against Syk and potently inhibits the BCR signaling pathway, as measured by inhibition of CD69 upregulation on primary human B-cells (IC50 = 48 nM). In addition, 14 inhibits cyto-kine release from mast cells, monocytes/macrophages, and neutrophils
Figure 3 Syk inhibitors.
with EC50's ranging from 33 to 158 nM . Crystal structures of the R406-Syk complex show that the aminopyrimidine group forms hydrogen bonds with hinge residue A451 and an aromatic CH-O interaction with E449. The pyrido-oxazinone nitrogens form H-bonds to water molecules and do not interact directly with the protein [71,72].
In an ascending dose Phase IIa study (TASKi1), R788 achieved a significant and dose-related clinical response, with 72% of patients in the 150 mg/bid group achieving ACR20 response compared to 38% on placebo . This efficacy correlated with a reduction in IL-6 and MMP-3 levels. In a Phase IIb trial (TASKi2) in methotrexate failures, R788 showed clinical improvement after 1 week and sustained efficacy thereafter, with 43% of patients achieving ACR50 response (placebo = 19%) after 6 months of dosing at 100 mg/bid . In the subsequent TASKi3 trial, however, ACR scores for R788 were not significantly different from placebo, although MRI scans did show improvements in synovitis and osteitis. The most common adverse effects were diarrhea, hypertension, and neutropenia. In a Phase II trial for refractory ITP, R788 increased and maintained platelet count in 50% of patients. Efficacy increased with dose, as did gastrointestinal adverse events . It is unclear if off-target effects may contribute to efficacy or the reported adverse events, as limited selectivity data has been disclosed [71,76].
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