Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis
| العنوان: | Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis |
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| المؤلفون: | Alain Monjardet, Thierry Christophe, Nicolas Triballeau, Helene Jary, Luke Jonathan Alvey, Romain Luc Marie Gosmini, Frédéric André De Ceuninck, Pierre Deprez, Robert Touitou, Roland Blanque, D. Amantini, Nele Vandervoort, Ellen van der Aar, Philip Leonard, F. Brebion, Patrick Mollat, Natacha Bienvenu, C. Cottereaux, I. Botez, Varin Marie Laurence Claire, Christophe Peixoto |
| المصدر: | Journal of Medicinal Chemistry. 64:2937-2952 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cartilage, Articular, Models, Molecular, Osteoarthritis, Pharmacology, 01 natural sciences, law.invention, Glycosaminoglycan, Mice, 03 medical and health sciences, Dogs, law, Drug Discovery, medicine, Animals, Humans, IC50, Aggrecan, Glycosaminoglycans, 030304 developmental biology, Aggrecanase, 0303 health sciences, Chemistry, Cartilage, ADAMTS, medicine.disease, Rats, 0104 chemical sciences, Mice, Inbred C57BL, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, Recombinant DNA, Molecular Medicine, ADAMTS5 Protein |
| الوصف: | 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). |
| تدمد: | 1520-4804 0022-2623 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e63e1d09bcd2c3ffc719892459e89ab3Test https://doi.org/10.1021/acs.jmedchem.0c02008Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e63e1d09bcd2c3ffc719892459e89ab3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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