GLPG1972 (Aldumastat, S201086) is a potent and selective small-molecule inhibitor of ADAMTS5 with IC50 of 19 and <23 nM against human and rat ADAMTS5, respectively.
GLPG1972 displayed 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases (MMPS and ADAM17/TACE).
GLPG1972 dose-dependently inhibited the IL-α stimulated GAG release with IC50 of <1.5 uM in mouse cartilage explants.
GLPG1972 dose-dependently inhibited AGNx1 release induced by IL-1β with IC50 of <1 uM in human articular cartilage explants, with no effect on the release of the MMP-driven generation of the AGNx2 neoepitope.
GLPG1972/S201086 (30-120 mg/kg b.i.d) reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%) in DMM mice.
GLPG1972/S201086 (10-50 mg/kg b.i.d) reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%) in MNX rats.