Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5

被引：20

作者：

Clement-Lacroix, P. ^{[1
]}

Little, C. B. ^{[2
]}

Smith, M. M. ^{[2
]}

Cottereaux, C. ^{[1
]}

Merciris, D. ^{[1
]}

Meurisse, S. ^{[1
]}

Mollat, P. ^{[1
]}

Touitou, R. ^{[1
]}

Brebion, F. ^{[1
]}

Gosmini, R. ^{[1
]}

De Ceuninck, F. ^{[3
]}

Botez, I ^{[3
]}

Lepescheux, L. ^{[1
]}

van der Aar, E. ^{[4
]}

Christophe, T. ^{[4
]}

Vandervoort, N. ^{[4
]}

Blanque, R. ^{[1
]}

Comas, D. ^{[1
]}

Deprez, P. ^{[1
]}

Amantini, D. ^{[1
]}

机构：

[1] Galapagos SASU, Romainville, France

[2] Univ Sydney, Royal North Shore Hosp, Kolling Inst, Northern Sydney Local Hlth Dist,Raymond Purves Bo, St Leonards, NSW, Australia

[3] Inst Rech Servier, Suresnes, France

[4] Galapagos NV, Mechelen, Belgium

来源：

OSTEOARTHRITIS AND CARTILAGE | 2022年 / 30卷 / 02期

关键词：

ADAMTS5; Aggrecanase; DMOAD; GENERATED AGGRECAN FRAGMENTS; MATRIX-METALLOPROTEINASE; CARTILAGE DEGRADATION; MURINE MODEL; MECHANICAL ALLODYNIA; SYNOVIAL-FLUID; DEFICIENT MICE; JOINT DAMAGE; OSTEOARTHRITIS; DISCOVERY;

D O I：

10.1016/j.joca.2021.08.012

中图分类号：

R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学（修复外科学）];

学科分类号：

100224 [整形外科学];

摘要：

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-1 alpha-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1 beta-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 mu M and 10 mu M, 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 (similar to 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. (C) 2021 Galapagos NV. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

引用

页码：291 / 301

页数：11

共 51 条

[31]

Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair [J].