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

被引：51

作者：

Brebion, Franck ^{[1
]}

Gosmini, Romain ^{[1
]}

Deprez, Pierre ^{[1
]}

Varin, Marie ^{[1
]}

Peixoto, Christophe ^{[1
]}

Alvey, Luke ^{[1
]}

Jary, Helene ^{[1
]}

Bienvenu, Natacha ^{[1
]}

Triballeau, Nicolas ^{[1
]}

Blanque, Roland ^{[1
]}

Cottereaux, Celine ^{[1
]}

Christophe, Thierry ^{[2
]}

Vandervoort, Nele ^{[2
]}

Mollat, Patrick ^{[1
]}

Touitou, Robert ^{[1
]}

Leonard, Philip ^{[3
]}

De Ceuninck, Frederic ^{[4
]}

Botez, Iuliana ^{[5
]}

Monjardet, Alain ^{[1
]}

van der Aar, Ellen ^{[2
]}

Amantini, David ^{[1
]}

机构：

[1] Galapagos SASU, F-93230 Romainville, France

[2] Galapagos NV, B-2800 Mechelen, Belgium

[3] Charles River, Struct Biol, Saffron Walden CB10 1XL, Essex, England

[4] Inst Rech Servier, Ctr Therapeut Innovat, Immunoinflammatory Dis, F-78290 Croissy Sur Seine, France

[5] Inst Rech Servier, Chem Ctr Excellence, F-78290 Croissy Sur Seine, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 06期

关键词：

D O I：

10.1021/acs.jmedchem.0c02008

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 mu M). 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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页码：2937 / 2952

页数：16

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