Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics.

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

Zinc-oxaprozin compounds: Synthesis, structure and biological activity.

Four novel zinc complexes, namely [Zn(oxa)2(MeOH)4] (1), [Zn(oxa)2(H2O)(bipy)]·MeOH·2.5H2O (2·MeOH·2.5H2O), [Zn(oxa)2(bipyam)]·1.25MeOH (3·1.25MeOH) and [Zn(oxa)2(phen)] (4), with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) and a N,N'-donor heterocyclic ligand, such as 2,2'­bipyridylamine (bipyam), 1,10­phenanthroline (phen) or 2,2'­bipyridine (bipy), were characterized with physicochemical techniques, various spectroscopies and single-crystal X-ray crystallography. In these coordination compounds, the oxaprozin ligands are coordinated to zinc ion in a monodentate or a bidentate chelating binding mode. The antioxidant activity of the complexes was evaluated via their ability to scavenge in vitro 1,1­diphenyl­2­picrylhydrazyl, hydroxyl and 2,2'­azinobis­(3­ethylbenzothiazoline­6­sulfonic acid) radicals. The complexes bind to calf-thymus DNA via intercalation as suggested via a series of studies employing UV-vis spectroscopy, DNA-viscosity measurements and competition with ethidium bromide. The complexes may bind to serum albumins tightly and reversibly in order to get transferred through the bloodstream.

Oxaprozin: A new hope in the modulation of matrix metalloproteinase 9 activity.

Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory disorders is well known. The aim of this study was to investigate the ability of oxaprozin to modulate the activity of matrix metalloproteinase 9 (MMP-9), a zinc-dependent endopeptidase involved in a wide range of physiological and pathological events associated with extracellular matrix (ECM) remodelling. The interaction between oxaprozin and MMP-9 was firstly investigated in silico by molecular docking and analysis with LIGPLOT software. Subsequently, the potential inhibitory activity of oxaprozin against MMP-9 and the possible mechanism of the ligand-enzyme interaction were investigated in vitro. Taking into account the in silico findings, MMP-9 can be considered a potential target of oxaprozin, which seems to be able to chelate the catalytic zinc ion through the nitrogen of the oxazole ring and the carboxylate moiety. Moreover, one of the phenyl rings interact with the S1' inhibitor-binding pocket through hydrophobic interaction. Gelatin zymography and enzymatic inhibition assay confirmed the potential role of oxaprozin as a competitive inhibitor of MMP-9. These observations sound particularly interesting if we consider the pathological role of MMP-9, especially evident in inflammatory conditions and cancer. This work may represent a starting point to improve the understanding of the role of oxaprozin, as well as its structural analogues, in modulating the MMP-9 function.