RA03546849 (CSF1Rinh, GENZ-882706) is a CNS-penetrant, potent and selective small-molecule CSF1R inhibitor, binds to CSF1R in a DFG-out conformation.
RA03546849 is highly selective for CSF1R as compared to other kinases with a selectivity score of S(35)=0.005, sCSF1Rinh exhibited excellent pharmacokinetic properties including good oral bioavailability and CNS penetrance.
sCSF1Rinh (500 nM) blocks these phosphorylation events in CSF1 (100 ng/mL) stimulation of BV2 microglia.
sCSF1Rinh inhibited murine bone marrow-derived macrophage proliferation with IC50 of 22 nM, sCSF1Rinh significantly depletes microglia in a concentration-dependent manner in murine mixed glial cultures (IC50=188 nM).
sCSF1Rinh reduced the number of microglia and infiltrating macrophages in an acute LPS model, with diminished microglial/macrophage proliferation and attenuated inflammatory response.
sCSF1Rinh also suppressed a deleterious microglial response in the C57BL/6 EAE (experimental autoimmune encephalomy) model as well as the MOG peptide-induced non-obese diabetic EAE model of progressive MS (NOD-EAE) and improved neurological impairments in both models.