Oxaprozin

Oxaprozin: A new hope in the modulation of matrix metalloproteinase 9 activity.[Pubmed:30582279]

Chem Biol Drug Des. 2018 Dec 23.

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.

Oxaprozin prodrug as safer nonsteroidal anti-inflammatory drug: Synthesis and pharmacological evaluation.[Pubmed:29283449]

Arch Pharm (Weinheim). 2018 Feb;351(2).

Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In order to circumvent the GI complications, Oxaprozin was amended as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. Dextran of average molecular weight (60,000-90,000 Da) was exploited as a carrier in the process of Oxaprozin prodrug production by esterification. The structural profiles of the synthesized Oxaprozin prodrug were characterized by FT-IR and NMR spectroscopy. The Oxaprozin prodrug possessed optimal molecular weight, lipophilicity, partition coefficient, protein binding, and degree of substitution of 52.4%. The release of Oxaprozin upon hydrolysis of the prodrug in both simulated gastric fluid and simulated intestinal fluid followed first-order kinetics with 55.2 min of half-life. Varied ADME properties of the prodrug resulted upon Schrodinger's QikProp tool application. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a remarkable decrease in the ulcer index and being devoid of antigenicity in experimental animals. Thus, it is evident that Oxaprozin prodrug is a safer oral NSAID without causing any ulcerations.

Comparison of liposomal and NLC (nanostructured lipid carrier) formulations for improving the transdermal delivery of oxaprozin: Effect of cyclodextrin complexation.[Pubmed:27825863]

Int J Pharm. 2016 Dec 30;515(1-2):684-691.

The combined strategy of drug-cyclodextrin (CD) complexation and complex loading into nanocarriers (deformable liposomes or nanostructured lipid carriers (NLC)), was exploited to develop effective topical formulations for Oxaprozin transdermal administration. Oxaprozin was loaded as ternary complex with randomly-methylated-ssCD and arginine, selected as the best system in improving drug solubility. The colloidal dispersions, characterized for particle size, zeta-potential and entrapment efficiency, were investigated for drug permeation properties in comparison with a plain drug aqueous suspension, a ternary complex aqueous solution and a plain drug liposomal or NLC dispersion. Experiments with artificial membranes showed that the joined use of CD and both liposomes or NLC enabled a marked increase of the drug permeability (16 and 8 times, respectively) and was significantly more effective (P<0.05) than the drug as ternary complex (3.2 times increase), and the corresponding liposomal or NLC dispersion of plain drug (5.6 and 4.3 times increase, respectively). Experiments with excised human skin confirmed the significantly (P<0.05) better performance of deformable liposomes than NLC in promoting drug permeation; moreover, they evidenced a more marked permeability increase compared to the plain drug (24 and 12 fold, respectively), attributed to a possible enhancer effect of the nanocarriers components and/or of the randomly-methylated-ssCD.

Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-diaryloxazoles.[Pubmed:27441569]

J Org Chem. 2016 Nov 4;81(21):10521-10526.

2-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The corresponding alpha-sulfonyl anion reacts smoothly with diverse alkyl halides giving monoalkylated (47-90%), dialkylated (50-97%), and cyclic (59-93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products in the range of 66-97%. The anti-inflammatory Oxaprozin was prepared using the alpha-sulfonyl carbanion strategy along with optimized desulfonylation.

Synthesis of extended oxazoles II: Reaction manifold of 2-(halomethyl)-4,5-diaryloxazoles.[Pubmed:26989270]

Tetrahedron Lett. 2016 Feb 17;57(7):757-759.

2-(Halomethyl)-4,5-diphenyloxazoles are effective, reactive scaffolds which can be utilized for synthetic elaboration at the 2-position. Through substitution reactions, the chloromethyl analogue is used to prepare a number of 2-alkylamino-, 2-alkylthio- and 2-alkoxy-(methyl) oxazoles. The 2-bromomethyl analogue offers a more reactive alternative to the chloromethyl compounds and is useful in the C-alkylation of a stabilized (malonate) carbanion as exemplified by a concise synthesis of Oxaprozin.

Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects.[Pubmed:26350105]

Pharm Res. 2016 Feb;33(2):301-14.

PURPOSE: Nanostructured Lipid Carriers (NLCs) loading Oxaprozin were developed to address an effective drug packaging and targeted delivery, improving the drug pharmacokinetics and pharmacodynamics properties and avoiding the local gastric side-effects. Macrophages actively phagocyte particles with sizes larger than 200 nm and, when activated, over-express folate beta receptors - features that in the case of this work constitute the basis for passive and active targeting strategies. METHODS: Two formulations containing Oxaprozin were developed: NLCs with and without folate functionalization. In order to target the macrophages folate receptors, a DSPE-PEG2000-FA conjugate was synthesized and added to the NLCs. RESULTS: These formulations presented a relatively low polydispersity index (approximately 0.2) with mean diameters greater than 200 nm and zeta potential inferior to -40 mV. The encapsulation efficiency of the particles was superior to 95% and the loading capacity was of 9%, approximately. The formulations retained the Oxaprozin release in simulated gastric fluid (only around 10%) promoting its release on simulated intestinal fluid. MTT and LDH assays revealed that the formulations only presented cytotoxicity in Caco-2 cells for Oxaprozin concentrations superior to 100 muM. Permeability studies in Caco-2 cells shown that Oxaprozin encapsulation did not interfered with Oxaprozin permeability (around 0.8 x 10(-5) cm/s in simulated intestinal fluid and about 1.45 x 10(-5) cm/s in PBS). Moreover, in RAW 264.7 cells NLCs functionalization promoted an increased uptake over time mainly mediated by a caveolae uptake mechanism. CONCLUSIONS: The developed nanoparticles enclose a great potential for Oxaprozin oral administration with significant less gastric side-effects.

Oxaprozin is an inhibitor of both COX-1 and COX-2 with IC50s of 2.2 μM and 36 μM for human platelet COX-1 and IL-1-stimulated human synovial cell COX-2, respectively. Oxaprozin also inhibits the activation of NF-κB.

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