BR103354 (BR 103354) is a novel potent, selective, oral fibroblast activation protein (FAP) inhibitor with IC50 of 14 nM.
BR103354 displays high selectivity against other related proteases with a selectivity index (SI) of 27.6 against PREP (PREP IC50=387 nM).
BR103354 (0.4 uM) blocked FAP-mediated cleavage of hFGF21 in cell-free assays; In differentiated 3T3/L1 adipocytes, the addition of FAP diminished hFGF21-induced Glut1 and phosphorylated levels of ERK, which were restored by BR103354.
BR103354 exhibited good pharmacokinetic properties as evidenced by oral bioavailability of 48.4% and minimal hERG inhibition.
BR103354 reduced nonfasting blood glucose concentrations with improved glucose tolerance and with reduced triglyceride (TG) content in liver of ob/ob mice, improved hepatic steatosis and fibrosis in NASH mouse model.
