GLPG-0634

A potent JAK1/JAK2 inhibitor with IC50 of 10 nM/28 nM in biochemical assays; less potent for JAK3 and TYK2; reveals a selectivity of 30-fold for JAK1- over JAK2-dependent signaling in cellular and whole blood assays; inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro; shows efficacy in the collagen-induced arthritis models and orally active.Rheumatoid Arthritis Phase 3 Clinical (In Vitro) :Filgotinib (GLPG0634) dose-dependently inhibits the differentiation of Th2 cells mediated by IL-4, a cytokine that signals through JAK1 and JAK3. Filgotinib also inhibits Th1 differentiation with similar potencies of 1 μM or lower. Filgotinib (GLPG0634) does not inhibit JAK2 homodimer-mediated signaling induced by EPO or PRL (IC50 > 10 μM) . (In Vivo) :Filgotinib (GLPG0634; 3, 10, 30 mg/kg, p.o.) dose-dependently prevents disease progression in the therapeutic rat CIA model. Filgotinib (50 mg/kg, o.p.) protects bone and cartilage from degradation, effectively reduces infiltration of T cells (CD3+ cells) and macrophages (F4/80+ cells) in the paw, and decreases the serum levels of all cytokines and chemokines measured, including IL-6, IP-10, XCL1, and MCP-1. Filgotinib (GLPG0634; 0.1 and 0.3 mg/kg) shows efficacy in the rat CIA model.