Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis
Franck Brebion, Romain Gosmini, Pierre Deprez, Marie Varin, Christophe Peixoto, Luke Alvey, Hélène Jary, Natacha Bienvenu, Nicolas Triballeau, Roland Blanque, Céline Cottereaux, Thierry Christophe, Nele Vandervoort, Patrick Mollat, Robert Touitou, Philip Leonard, Frédéric De Ceuninck, Iuliana Botez, Alain Monjardet, Ellen van der Aar, David Amantini, Franck Brebion, Romain Gosmini, Pierre Deprez, Marie Varin, Christophe Peixoto, Luke Alvey, Hélène Jary, Natacha Bienvenu, Nicolas Triballeau, Roland Blanque, Céline Cottereaux, Thierry Christophe, Nele Vandervoort, Patrick Mollat, Robert Touitou, Philip Leonard, Frédéric De Ceuninck, Iuliana Botez, Alain Monjardet, Ellen van der Aar, David Amantini
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).
Source: PubMed