BMS-986143, an orally active, reversible BTK inhibitor with an IC50 value of 0.26 nM, is designed for autoimmune disease research. Additionally, it targets TEC, BLK, BMX, TXK, FGR, YES1, and ITK, exhibiting IC50s of 3 nM, 5 nM, 7 nM, 10 nM, 15 nM, 19 nM, and 21 nM, respectively [1].

BMS-986143 effectively inhibits Bruton's tyrosine kinase (BTK) activity, demonstrating potent inhibitory effects across a variety of assays. Notably, it shows IC50 values of 6.9±3.4 nM in Ramos cellular assays and 25±19 nM in human whole blood assays. Further, it significantly inhibits signaling related to IgG-containing immune complex activation via low-affinity Fcγ receptors in peripheral blood mononuclear cells (PBMC) with an IC50 of 2 nM. Additionally, BMS-986143 suppresses CD63 expression on basophils in response to FcεRI signaling in human whole blood (IC50=54 nM) and inhibits calcium flux, proliferation of human peripheral B Cells, CD86 surface expression in peripheral B Cells, and TNFα production in human PBMC Cells with IC50 values of 7±3, 1±0.4, 1±0.5, and 2 nM, respectively.

BMS-986143 demonstrates effective treatment in mouse models of both collagen-induced arthritis (CIA) and anticollagen antibody-induced arthritis (CAIA), showcasing high oral bioavailability in mice (100%) and dogs (82%), and moderate peak plasma concentrations (Cmax) of 4.3 μM in mice and 1.2 μM in dogs when administered orally at doses of 6 mg/kg for mice and 2 mg/kg for dogs. It also has prolonged elimination half-lives of 3.6 hours in mice and 7.9 hours in dogs, attributable to its moderate plasma clearance rates (8.6 mL/min/kg for mice and 4.4 mL/min/kg for dogs) and low distribution volumes (1.8 L/kg for mice and 2.6 L/kg for dogs), after intravenous doses of 3.0 mg/kg for mice and 1.0 mg/kg for dogs. In trials with DBA/1 male mice aged 8-10 weeks exhibiting CIA, oral administration of BMS-986143 at 15 and 45 mg/kg twice daily resulted in dose-dependent reduction of clinical disease progression (63% and 80% inhibition, respectively), corresponding to 17 and 19 hours of effective coverage based on the mouse whole blood IC50 of 130 nM.