ABSTRACT
PURPOSE: The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters. METHODS: FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats. RESULTS: The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 Ā± 6.8Ā nm, 0.133 Ā± 0.030 and - 30.4 Ā± 0.7Ā mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the Cmax of FB-NS gel was 2.5 times higher than the reference gel, while AUC0-24 was 2.96 times higher. CONCLUSION: FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Delivery Systems/methods , Drug Development/methods , Flurbiprofen/pharmacokinetics , Nanoparticles/metabolism , Skin Absorption/physiology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Drug Liberation/physiology , Flurbiprofen/administration & dosage , Flurbiprofen/chemical synthesis , Male , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Organ Culture Techniques , Particle Size , Rats , Rats, Wistar , Skin Absorption/drug effects , Suspensions , X-Ray Diffraction/methodsABSTRACT
The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCĆ®ĀĀCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCĆ®ĀĀCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCĆ®ĀĀCCH(OH)CH3 and TMSCĆ®ĀĀCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner.
Subject(s)
Alkynes/chemistry , Copper/chemistry , Flurbiprofen/chemical synthesis , Indicators and Reagents/chemistry , Propanols/chemistry , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Catalysis , Flurbiprofen/chemistry , Flurbiprofen/pharmacology , StereoisomerismABSTRACT
Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.
Subject(s)
Amides/pharmacology , Amidohydrolases/antagonists & inhibitors , Analgesics/pharmacology , Cyclooxygenase 2/metabolism , Enzyme Inhibitors/pharmacology , Flurbiprofen/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amidohydrolases/metabolism , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Male , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Structure , Quantum Theory , Rats , Rats, Sprague-Dawley , Rats, Wistar , Static Electricity , Structure-Activity RelationshipABSTRACT
A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps.
Subject(s)
Flurbiprofen , Naproxen , Palladium/chemistry , Catalysis , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Naproxen/chemical synthesis , Naproxen/chemistryABSTRACT
Novel derivatives of flurbiprofen 1-18 including flurbiprofen hydrazide 1, substituted aroyl hydrazides 2-9, 2-mercapto oxadiazole derivative 10, phenacyl substituted 2-mercapto oxadiazole derivatives 11-15, and benzyl substituted 2-mercapto oxadiazole derivatives 16-18 were synthesized and characterized by EI-MS, 1H and 13C NMR spectroscopic techniques. All derivatives 1-18 were screened for α-amylase inhibitory activity and demonstrated a varying degree of potential ranging from IC50Ć¢ĀĀÆ=Ć¢ĀĀÆ1.04Ć¢ĀĀÆĀ±Ć¢ĀĀÆ0.3 to 2.41Ć¢ĀĀÆĀ±Ć¢ĀĀÆ0.09Ć¢ĀĀÆĀµM as compared to the standard acarbose (IC50Ć¢ĀĀÆ=Ć¢ĀĀÆ0.9Ć¢ĀĀÆĀ±Ć¢ĀĀÆ0.04Ć¢ĀĀÆĀµM). Out of eighteen compounds, derivatives 2 (IC50Ć¢ĀĀÆ=Ć¢ĀĀÆ1.69Ć¢ĀĀÆĀ±Ć¢ĀĀÆ0.1Ć¢ĀĀÆĀµM), 3 (IC50Ć¢ĀĀÆ=Ć¢ĀĀÆ1.04Ć¢ĀĀÆĀ±Ć¢ĀĀÆ0.3Ć¢ĀĀÆĀµM), 9 (IC50Ć¢ĀĀÆ=Ć¢ĀĀÆ1.25Ć¢ĀĀÆĀ±Ć¢ĀĀÆ1.05Ć¢ĀĀÆĀµM), and 13 (IC50Ć¢ĀĀÆ=Ć¢ĀĀÆ1.6Ć¢ĀĀÆĀ±Ć¢ĀĀÆ0.18Ć¢ĀĀÆĀµM) found to be excellent inhibitors while rest of the compounds demonstrated comparable inhibition potential. A limited structure-activity relationship (SAR) was established by looking at the varying structural features of the library. In addition to that, in silico study was conducted to understand the binding interactions of the compounds (ligands) with the active site of α-amylase enzyme.
Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Flurbiprofen/pharmacology , alpha-Amylases/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , alpha-Amylases/metabolismABSTRACT
Cobalt catalysts with electronically enhanced site selectivity have been developed, as evidenced by the high ortho-to-fluorine selectivity observed in the C(sp2)-H borylation of fluorinated arenes. Both the air-sensitive cobalt(III) dihydride boryl 4-Me-(iPrPNP)Co(H)2BPin (1) and the air-stable cobalt(II) bis(pivalate) 4-Me-(iPrPNP)Co(O2CtBu)2 (2) compounds were effective and exhibited broad functional group tolerance across a wide range of fluoroarenes containing electronically diverse functional groups, regardless of the substitution pattern on the arene. The electronically enhanced ortho-to-fluorine selectivity observed with the cobalt catalysts was maintained in the presence of a benzylic dimethylamine and hydrosilanes, overriding the established directing-group effects observed with precious-metal catalysts. The synthetically useful selectivity observed with cobalt was applied to an efficient synthesis of the anti-inflammatory drug flurbiprofen.
Subject(s)
Alkenes/chemistry , Boron/chemistry , Cobalt/chemistry , Iridium/chemistry , Air , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Catalysis , Drug Stability , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Halogenation , Molecular StructureABSTRACT
The current structure-activity relationship of profens (i.e., 2-arylpropionic acid derivatives, a class of non-steroidal anti-inflammatory drugs) discusses the importance of α-monomethyl substitution on these compounds, since the activities obtained through their corresponding arylacetic acid derivatives (i.e., α-demethylated derivatives) or α,α-dimethyl-substituted compounds are less than what is observed for the parent profens. Unfortunately, this implies a generalization in structure-activity relationships of profens in such a way that a mono-(non-methyl)alkyl group or dialkyl substituent replaced at the α-position of a profen analogue results in abolished activity. Therefore, within this study, we aimed to question this generalization employing ibuprofen, flurbiprofen, and naproxen as model compounds. A series of α-(non-methyl)alkyl-substituted ibuprofen and flurbiprofen analogues as well as α,α-dialkyl-substituted ibuprofen, flurbiprofen, and naproxen derivatives were synthesized and screened for their potential to inhibit cyclooxygenase enzymes. In addition, since profens have negligible potential to inhibit lipoxygenase enzymes, the effect of such derivatization was also questioned in lipoxygenase inhibition assays. The findings only partially agreed with the current structure-activity approach of profens and the activity results of some compounds were found as beyond ordinary.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Drug Design , Propionates/chemical synthesis , Propionates/pharmacology , Arachidonate 5-Lipoxygenase/metabolism , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Flurbiprofen/chemical synthesis , Flurbiprofen/pharmacology , Ibuprofen/analogs & derivatives , Ibuprofen/chemical synthesis , Ibuprofen/pharmacology , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Molecular Structure , Naproxen/chemical synthesis , Naproxen/pharmacology , Structure-Activity RelationshipABSTRACT
To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.
Subject(s)
Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Flurbiprofen/analogs & derivatives , Nitrates/chemistry , Nitric Oxide/metabolism , Tacrine/analogs & derivatives , Vasodilator Agents/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Binding Sites , Butyrylcholinesterase/metabolism , Catalytic Domain , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Flurbiprofen/metabolism , Kinetics , Nitrates/chemical synthesis , Nitrates/metabolism , Protein Binding , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistry , Tacrine/metabolism , Vasodilator Agents/chemical synthesis , Vasodilator Agents/metabolismABSTRACT
Five tacrine-flurbiprofen hybrid compounds (3a-e) were synthesized as multi-target-directed compounds for the treatment of Alzheimer's disease. Compared to tacrine, two compounds (3d and 3e) showed better acetylcholinesterase (AChE) inhibitory activity and others (3b-e) better or the same butyrylcholinesterase (BuChE) inhibitory activity. Notably, 3d showed a mixed-type inhibitory action for AChE, indicating a "dual-binding site action" of both toward the catalytic active site (CAS) and the peripheral anionic site (PAS), whereas for BuChE, a competitive inhibitory action was observed. Furthermore, a cell-based assay on amyloid-Ć inhibition demonstrated that the selected target compound 3d effectively inhibits the formation of amyloid-Ć in vitro.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Flurbiprofen/pharmacology , Tacrine/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Catalytic Domain , Cells, Cultured , Cholinesterase Inhibitors/chemical synthesis , Female , Flurbiprofen/analogs & derivatives , Flurbiprofen/chemical synthesis , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Protein Conformation , Rats , Rats, Wistar , Structure-Activity Relationship , Tacrine/analogs & derivatives , Tacrine/chemical synthesisABSTRACT
Alzheimer's disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate ĆĀ³-secretase, reducing Ć amyloid (AĆ) levels, have been considered as potential therapeutics for AD. Among these the (R)-enantiomer of flurbiprofen (FLU) seems to be very promising, but it shows low brain penetration. In this study, in order to improve the properties of FLU against Alzheimer's pathogenesis we synthesized some novel FLU lipophilic analogues. Lipophilicity of the new molecules has been characterized in terms of clogP, log K(C18/W) and log K(IAM/W) values. Permeability has been determined in both gastrointestinal PAMPA (PAMPA-GI) at different pH values and in brain blood barrier PAMPA (PAMPA-BBB) models. They were also tested for their ability to inhibit in vitro ĆĀ³-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce AĆ 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.
Subject(s)
Amyloid beta-Peptides/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Flurbiprofen/analogs & derivatives , Flurbiprofen/chemical synthesis , Peptide Fragments/metabolism , Alzheimer Disease/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Astrocytes/drug effects , Astrocytes/metabolism , Blood-Brain Barrier , Cell Line , Cells, Cultured , Drug Evaluation, Preclinical , Flurbiprofen/pharmacology , Humans , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Membranes, Artificial , Models, Biological , Permeability , Rats , StereoisomerismABSTRACT
Benzylic functionalization is a convenient approach towards the conversion of readily available aromatic hydrocarbon feedstocks into more useful molecules. However, the formation of carbanionic benzyl species from benzyl halides or similar precursors is far from trivial. An alternative approach is the direct reaction of a styrene with a suitable coupling partner, but these reactions often involve the use of precious-metal transition-metal catalysts. Herein, we report the facile and convenient generation of reactive benzyl anionic species from styrenes. A Cu(I)-catalyzed Markovnikov hydroboration of the styrenic double bond by using a bulky pinacol borane source is followed by treatment with KOtBu to facilitate a sterically induced cleavage of the C-B bond to produce a benzylic carbanion. Quenching this intermediate with a variety of electrophiles, including CO(2), CS(2), isocyanates, and isothiocyanates, promotes C-C bond formation at the benzylic carbon atom. The utility of this methodology was demonstrated in a three-step, two-pot synthesis of the nonsteroidal anti-inflammatory drug (Ā±)-flurbiprofen.
Subject(s)
Benzyl Compounds/chemistry , Flurbiprofen/chemistry , Flurbiprofen/chemical synthesis , Styrenes/chemistry , Catalysis , Molecular StructureABSTRACT
The first Suzuki-Miyaura cross-couplings of carbamates, carbonates, and sulfamates is described. The method provides a powerful means of using simple derivatives of phenol as precursors to polysubstituted aromatic compounds, as exemplified by a concise synthesis of the anti-inflammatory drug flurbiprofen.
Subject(s)
Carbamates/chemical synthesis , Carbonates/chemical synthesis , Flurbiprofen/chemical synthesis , Sulfonic Acids/chemical synthesis , Carbamates/chemistry , Carbonates/chemistry , Flurbiprofen/chemistry , Molecular Structure , Stereoisomerism , Sulfonic Acids/chemistrySubject(s)
Acetates/chemistry , Halogens/chemistry , Mesylates/chemistry , Palladium/chemistry , Anastrozole , Catalysis , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Nitriles/chemical synthesis , Nitriles/chemistry , Salts/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/pharmacology , Flurbiprofen/chemical synthesis , Flurbiprofen/pharmacology , Models, Molecular , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Administration, Oral , Albumins , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antioxidants/administration & dosage , Antioxidants/chemical synthesis , Antioxidants/chemistry , Carrageenan , Edema/chemically induced , Edema/drug therapy , Female , Flurbiprofen/administration & dosage , Flurbiprofen/chemistry , Humans , Inflammation/chemically induced , Inflammation/drug therapy , Male , Mice , Molecular Structure , Prodrugs/administration & dosage , Prodrugs/chemistryABSTRACT
Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Flurbiprofen/analogs & derivatives , Flurbiprofen/chemical synthesis , Peptide Fragments/antagonists & inhibitors , Administration, Oral , Alzheimer Disease/blood , Alzheimer Disease/genetics , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood-Brain Barrier/metabolism , Caco-2 Cells , Cell Line, Tumor , Cell Membrane Permeability , Cyclooxygenase Inhibitors/pharmacology , Flurbiprofen/pharmacology , Glioma , Humans , Immunoassay , In Vitro Techniques , Injections, Intravenous , Mice , Mice, Transgenic , Peptide Fragments/blood , Peptide Fragments/metabolism , Rats , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis of a group of 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,3,4-thiadiazoles and 1,2,4-triazine derived from 2-(2-fluoro-4-biphenylyl) propionic acid is described. The structures of new compounds are supported by IR, 1H NMR and MS data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug flurbiprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. Five out of seventeen new compounds, showed very good anti-inflammatory activity in the carrageenan induced rat paw edema test with negligible ulcerogenic action. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA), which is one of the byproducts of lipid peroxidation. The study showed that the compounds inhibit the induction of gastric mucosal lesions and it can be suggested from our results that their protective effects may be related to an inhibition of lipid peroxidation in the gastric mucosa.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Propionates/chemical synthesis , Propionates/pharmacology , Animals , Carrageenan , Edema/chemically induced , Edema/prevention & control , Female , Flurbiprofen/analogs & derivatives , Flurbiprofen/chemical synthesis , Flurbiprofen/pharmacology , Foot/pathology , Indicators and Reagents , Lipid Peroxidation/drug effects , Male , Pain Measurement/drug effects , Rats , Rats, Wistar , Stomach Ulcer/chemically induced , Stomach Ulcer/pathologyABSTRACT
The flurbiprofen complex of copper(II) was prepared and characterized by IR, UV-VIS and EPR Spectroscopy, magnetic susceptibility, and thermogravimetric analysis. The compound was tested for in vivo anti-inflammatory and analgesic activities in rats. The inhibitory effect on carrageenin-induced paws inflammation and analgesic effect of copper flurbiprofen complex were similar to those of free flurbiprofen. However, the copper complex produced less gastric irritation than the parent drug.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Edema/drug therapy , Flurbiprofen/chemical synthesis , Flurbiprofen/pharmacology , Gastric Mucosa/physiology , Intestinal Mucosa/physiology , Analysis of Variance , Animals , Flurbiprofen/chemistry , Gastric Mucosa/drug effects , Intestinal Mucosa/drug effects , Male , Molecular Structure , Rats , Rats, Inbred Strains , Spectrophotometry, InfraredABSTRACT
In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug's metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4'-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/metabolism , Cunninghamella/metabolism , Fluorine/metabolism , Flurbiprofen/metabolism , Hydrocarbons, Fluorinated/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Crystallography, X-Ray , Cunninghamella/chemistry , Drug Design , Fluorine/chemistry , Flurbiprofen/chemical synthesis , Flurbiprofen/chemistry , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Models, Molecular , Molecular StructureABSTRACT
A series of new α-aryl propionic acid derivatives had been synthesized through different synthetic routes from the readily available 2-fluoronitrobenzene as key starter. The synthesized compounds were screened for their antiinflammatory activity using rat paw edema method. Azoles (6c, 6h and 6i) have showed considerable good antiinflammatory activity. The present series with some modification may serve as important core for the development of new anti-inflammatory agents.