Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS‑5 Inhibitor for the Treatment of Osteoarthritis

There are currently no approved disease-modifying osteoarthritis
(OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation
of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5
is a promising target for the identification of DMOADs. We describe
the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5
inhibitor obtained by optimization of a promising hydantoin series
following an HTS. Biochemical activity against rat and human ADAMTS-5
was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity
was confirmed with human aggrecan using an AGC ELISA. The most promising
compounds were selected based on reduction of glycosaminoglycan release
after interleukin-1 stimulation in mouse cartilage explants and led
to the discovery of GLPG1972/S201086. The anticatabolic activity was
confirmed in mouse cartilage explants (IC50 < 1.5 μM).
The cocrystal structure of GLPG1972/S201086 with human recombinant
ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a
phase 2 clinical study in patients with knee OA (NCT03595618).