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

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.
Franck Brebion 1,  Romain Gosmini 1,  Pierre Deprez 1,  Marie Varin 1,  Christophe Peixoto 1,  Luke Alvey 1,  Hélène Jary 1,  Natacha Bienvenu 1,  Nicolas Triballeau 1,  Roland Blanque 1,  Céline Cottereaux 1,  Thierry Christophe 2,  Nele Vandervoort 2,  Patrick Mollat 1,  Robert Touitou 1,  Philip Leonard 3,  Frédéric De Ceuninck 4,  Iuliana Botez 5,  Alain Monjardet 1,  Ellen van der Aar 2,  David Amantini 1
Affiliations

Affiliations

  • 1 Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • 2 Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 3 Structural Biology, Charles River, Chesterford Research Park, CB10 1XL Saffron Walden, United Kingdom.
  • 4 Institut de Recherches Servier, Center for Therapeutic Innovation, Immuno-inflammatory Disease, 78290 Croissy sur Seine, France.
  • 5 Institut de Recherches Servier, Chemistry Center of Excellence, 78290 Croissy sur Seine, France.
PMID: 33719441 DOI: 10.1021/acs.jmedchem.0c02008
Abstract

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).

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