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

Animals Humans Mice Rats ADAMTS5 Protein / antagonists & inhibitors Piperazines / chemistry
ADAMTS5 Aggrecanase DMOAD

Journal

Osteoarthritis and cartilage
ISSN: 1522-9653
Titre abrégé: Osteoarthritis Cartilage
Pays: England
ID NLM: 9305697

Informations de publication

Date de publication:
02 2022
Historique:
received: 15 03 2021
revised: 29 07 2021
accepted: 09 08 2021
pubmed: 10 10 2021
medline: 17 3 2022
entrez: 9 10 2021
Statut: ppublish

Résumé

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. 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. GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC 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.

Identifiants

DOI: 10.1016/j.joca.2021.08.012 PMID: 34626798
pubmed: 34626798
pii: S1063-4584(21)00918-3
doi: 10.1016/j.joca.2021.08.012
pii:
doi:

Substances chimiques

ADAMTS5 Protein EC 3.4.24.-
ADAMTS5 inhibitor GLPG1972 0
Piperazines 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

291-301

Informations de copyright

Copyright © 2021 Galapagos NV. Published by Elsevier Ltd.. All rights reserved.

Auteurs

P Clement-Lacroix (P)

Galapagos SASU, Romainville, France. Electronic address: Philippe.Clement-Lacroix@glpg.com.

C B Little (CB)

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.

M M Smith (MM)

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.

C Cottereaux (C)

Galapagos SASU, Romainville, France. Electronic address: Celine.Cottereaux@glpg.com.

D Merciris (D)

Galapagos SASU, Romainville, France. Electronic address: Didier.MERCIRIS@glpg.com.

S Meurisse (S)

Galapagos SASU, Romainville, France. Electronic address: Sandrine.Meurisse@glpg.com.

P Mollat (P)

Galapagos SASU, Romainville, France. Electronic address: Patrick.Mollat@glpg.com.

R Touitou (R)

Galapagos SASU, Romainville, France. Electronic address: Robert.Touitou@glpg.com.

F Brebion (F)

Galapagos SASU, Romainville, France. Electronic address: Franck.Brebion@glpg.com.

R Gosmini (R)

Galapagos SASU, Romainville, France. Electronic address: Romain.Gosmini@glpg.com.

F De Ceuninck (F)

Institut de Recherches Servier, France. Electronic address: frederic.deceuninck@servier.com.

I Botez (I)

Institut de Recherches Servier, France. Electronic address: iuliana.botez@servier.com.

L Lepescheux (L)

Galapagos SASU, Romainville, France. Electronic address: Lien.Lepescheux@glpg.com.

E van der Aar (E)

Galapagos NV, Mechelen, Belgium. Electronic address: Ellen.vanderAar@glpg.com.

T Christophe (T)

Galapagos NV, Mechelen, Belgium. Electronic address: Thierry.Christophe@glpg.com.

N Vandervoort (N)

Galapagos NV, Mechelen, Belgium. Electronic address: nele.vandervoort@glpg.com.

R Blanqué (R)

Galapagos SASU, Romainville, France. Electronic address: Roland.Blanque@glpg.com.

D Comas (D)

Galapagos SASU, Romainville, France. Electronic address: Daniel.Comas@glpg.com.

P Deprez (P)

Galapagos SASU, Romainville, France. Electronic address: Pierre.Deprez@glpg.com.

D Amantini (D)

Galapagos SASU, Romainville, France. Electronic address: David.Amantini@glpg.com.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Pharmacological characterization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Pharmacological characterization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Pharmacological characterization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Pharmacological characterization of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Scléroprotéines › Protéines de la matrice extracellulaire › Protéines ADAMTS › Protéine ADAMTS5 › Pharmacological characterization of...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipérazines › Pharmacological characterization of...