Kuriwaki I, et al. Bioorganic & Medicinal Chemistry, 2022, 59, 116657.
ASP5878 was designed as a pan-FGFR inhibitor with enhanced metabolic stability and minimized hERG channel inhibition. Optimization involved replacing the ethylene linker with an ether moiety and converting a phenyl group into a pyrazole ring, reducing π-π interactions with Phe656 in hERG. In vitro, ASP5878 potently inhibited FGFR3 enzyme activity and FGFR3-dependent cell proliferation. Autophosphorylation assays confirmed effective target engagement in vivo. Safety pharmacology studies employed patch-clamp hERG assays and single oral dosing in dogs (1-100 mg/kg) to assess cardiovascular, central nervous, and respiratory effects. Pharmacokinetic profiling demonstrated high oral bioavailability, moderate brain penetration, and low clearance in rats and dogs, supporting its utility in experimental FGFR3-targeted oncology studies.
