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

J Med Chem. 2021 Mar 25;64(6):2937-2952. doi: 10.1021/acs.jmedchem.0c02008. Epub 2021 Mar 15.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS5 Protein / antagonists & inhibitors*
  • ADAMTS5 Protein / metabolism
  • Animals
  • Cartilage, Articular / drug effects
  • Cartilage, Articular / metabolism
  • Dogs
  • Glycosaminoglycans / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Osteoarthritis / drug therapy*
  • Osteoarthritis / metabolism
  • Rats


  • Glycosaminoglycans
  • ADAMTS5 Protein

Associated data