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

Abstract

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-1a-stimulated glycosaminoglycan release in mouse femoral head cartilage explants, and on interleukin-1bstimulated 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 (IC 50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60e>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 mM and 10 mM, respectively). In DMM mice, GLPG1972/S201086 (30e120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23 e37%), cartilage structural damage (23e39%) and subchondral bone sclerosis (21e36%). In MNX rats, GLPG1972/S201086 (10e50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6 e23%), and decreased proteoglycan loss (~27%) and subchondral bone sclerosis (77e110%). 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.

Safety, Pharmacokinetics, and Pharmacodynamics of the ADAMTS‐5 Inhibitor GLPG1972/S201086 in Healthy Volunteers and Participants With Osteoarthritis of the Knee or Hip

“…22 Furthermore, GLPG1972 significantly reduced femorotibial cartilage proteoglycan loss, cartilage damage, and subchondral bone sclerosis in a mouse model of OA (ie, destabilization of the medial meniscus). 22 Early in vitro testing suggested that GLPG1972 is a potential cytochrome P450 (CYP) 3A4 inducer, a potential substrate of CYP3A4, and to a lesser extent of CYP2D6. Based on these in vitro results, 2 in vivo drug-drug interaction studies were conducted.…”

“… 22 Furthermore, GLPG1972 significantly reduced femorotibial cartilage proteoglycan loss, cartilage damage, and subchondral bone sclerosis in a mouse model of OA (ie, destabilization of the medial meniscus). 22 …”

“…22 In a meniscectomized rat model, GLPG1972 was associated with significant disease-modifying OA drug activity, as measured by a reduction in Osteoarthritis Research Society International score, and a significant impact on several histomorphometric parameters. 22 Furthermore, GLPG1972 significantly reduced femorotibial cartilage proteoglycan loss, cartilage damage, and subchondral bone sclerosis in a mouse model of OA (ie, destabilization of the medial meniscus). 22 Early in vitro testing suggested that GLPG1972 is a potential cytochrome P450 (CYP) 3A4 inducer, a potential substrate of CYP3A4, and to a lesser extent of CYP2D6.…”

“…19 GLPG1972/S201086, henceforth referred to as GLPG1972, is a small-molecule inhibitor of ADAMTS-5 being codeveloped by Galapagos and Servier, the chemical structure of which has been described by Brebion et al 20,21 Biochemical half maximal values for inhibition (IC 50 ) of human and rat ADAMTS-5 by GLPG1972 were 19 and <23 nM, respectively, while in mouse femoral head cartilage explants stimulated by interleukin-1α, glycosaminoglycan release was concentration-dependently inhibited with an IC 50 of 1.5 μM. 22 In human articular cartilage explants stimulated with interleukin-1β, generation of aggrecanase-derived aggrecan fragments was dosedependently inhibited by GLPG1972, with a mean estimated IC 50 <1 μM. 22 In a meniscectomized rat model, GLPG1972 was associated with significant disease-modifying OA drug activity, as measured by a reduction in Osteoarthritis Research Society International score, and a significant impact on several histomorphometric parameters.…”

“… 22 In human articular cartilage explants stimulated with interleukin‐1β, generation of aggrecanase‐derived aggrecan fragments was dose‐dependently inhibited by GLPG1972, with a mean estimated IC 50 <1 μM. 22 In a meniscectomized rat model, GLPG1972 was associated with significant disease‐modifying OA drug activity, as measured by a reduction in Osteoarthritis Research Society International score, and a significant impact on several histomorphometric parameters. 22 Furthermore, GLPG1972 significantly reduced femorotibial cartilage proteoglycan loss, cartilage damage, and subchondral bone sclerosis in a mouse model of OA (ie, destabilization of the medial meniscus).…”