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
  • 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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