Abstract
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 (IC50±SD: 19±2nM and <23±1nM, 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 20μM and 10μM, respectively). In DMM mice, GLPG1972/S201086 (30-120mg/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 (10-50mg/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%). 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.
Highlights
The majority of existing small-molecule aggrecanase inhibitors suffer from poor selectivity against other proteases and poor pharmacokinetics[17]
These limitations originate from the high homology present in the catalytic site across different matrix metalloproteinases (MMPs) families and from the use of notoriously problematic zinc-chelating groups such as hydroxamic acids
GLPG1972 at 10, 25 and 50 mg/kg b.i.d. reduced proteoglycan loss compared with vehicle (~27%; P < 0.05 at all doses)
Summary
P. Clement-Lacroix et al / Osteoarthritis and Cartilage xxx (xxxx) xxx. For osteoarthritis (OA), symptom relief through physical therapy, use of non-steroidal anti-inflammatory drugs (NSAIDs) or local injection of corticosteroids or viscosupplements are presently the only options before turning to joint replacement surgery. Progressive cartilage degradation, the hallmark of OA, results from an imbalance between synthesis and degradation of the extracellular matrix (ECM) proteins by proteases[2]. The inhibition of specific ECM-degrading enzymes is an attractive therapeutic strategy to deliver DMOADs3. Type II collagen and aggrecan are two of the major structural components of cartilage, which are degraded by specific matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), respectively. Clinical trials investigating broadspectrum MMP inhibitors as OA treatments reported unwanted side effects such as musculoskeletal pain[4], diminishing interest in this therapeutic class. ADAMTS activity has been identified as playing a crucial role in pathological aggrecanolysis, an early event in OA pathology[5,6]
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