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 μM).
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).
Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.
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.
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