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).
Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.
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