P Clement-Lacroix1, C B Little2, M M Smith3, C Cottereaux4, D Merciris5, S Meurisse6, P Mollat7, R Touitou8, F Brebion9, R Gosmini10, F De Ceuninck11, I Botez12, L Lepescheux13, E van der Aar14, T Christophe15, N Vandervoort16, R Blanqué17, D Comas18, P Deprez19, D Amantini20. 1. Galapagos SASU, Romainville, France. Electronic address: Philippe.Clement-Lacroix@glpg.com. 2. Raymond Purves Bone and Joint Research Laboratories, University of Sydney, Kolling Institute, Northern Sydney Local Health District, Royal North Shore Hospital, St Leonards, NSW, Australia. Electronic address: christopher.little@sydney.edu.au. 3. Raymond Purves Bone and Joint Research Laboratories, University of Sydney, Kolling Institute, Northern Sydney Local Health District, Royal North Shore Hospital, St Leonards, NSW, Australia. Electronic address: mobsmith@sydney.edu.au. 4. Galapagos SASU, Romainville, France. Electronic address: Celine.Cottereaux@glpg.com. 5. Galapagos SASU, Romainville, France. Electronic address: Didier.MERCIRIS@glpg.com. 6. Galapagos SASU, Romainville, France. Electronic address: Sandrine.Meurisse@glpg.com. 7. Galapagos SASU, Romainville, France. Electronic address: Patrick.Mollat@glpg.com. 8. Galapagos SASU, Romainville, France. Electronic address: Robert.Touitou@glpg.com. 9. Galapagos SASU, Romainville, France. Electronic address: Franck.Brebion@glpg.com. 10. Galapagos SASU, Romainville, France. Electronic address: Romain.Gosmini@glpg.com. 11. Institut de Recherches Servier, France. Electronic address: frederic.deceuninck@servier.com. 12. Institut de Recherches Servier, France. Electronic address: iuliana.botez@servier.com. 13. Galapagos SASU, Romainville, France. Electronic address: Lien.Lepescheux@glpg.com. 14. Galapagos NV, Mechelen, Belgium. Electronic address: Ellen.vanderAar@glpg.com. 15. Galapagos NV, Mechelen, Belgium. Electronic address: Thierry.Christophe@glpg.com. 16. Galapagos NV, Mechelen, Belgium. Electronic address: nele.vandervoort@glpg.com. 17. Galapagos SASU, Romainville, France. Electronic address: Roland.Blanque@glpg.com. 18. Galapagos SASU, Romainville, France. Electronic address: Daniel.Comas@glpg.com. 19. Galapagos SASU, Romainville, France. Electronic address: Pierre.Deprez@glpg.com. 20. Galapagos SASU, Romainville, France. Electronic address: David.Amantini@glpg.com.
Abstract
OBJECTIVE: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. METHODS: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1β-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. RESULTS: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 μM and 10 μM, respectively). In DMM mice, GLPG1972/S201086 (30-120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%). CONCLUSIONS: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.
OBJECTIVE: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. METHODS: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1β-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. RESULTS: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 μM and 10 μM, respectively). In DMM mice, GLPG1972/S201086 (30-120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%). CONCLUSIONS: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.
Authors: Tonia L Vincent; Tamara Alliston; Mohit Kapoor; Richard F Loeser; Linda Troeberg; Christopher B Little Journal: Clin Geriatr Med Date: 2022-05 Impact factor: 3.529
Authors: Ellen van der Aar; Henri Deckx; Sonia Dupont; Ann Fieuw; Stephane Delage; Staffan Larsson; André Struglics; L Stefan Lohmander; Agnes Lalande; Emilie Leroux; David Amantini; Paul Passier Journal: Clin Pharmacol Drug Dev Date: 2021-12-02