- High analgesic and anti-inflammatory in vivo activities of six new hybrids NSAIAs tetrahydropyran derivatives
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We present in this article syntheses of six new hybrids compounds (4-9) that were efficiently prepared in one or two steps (70-84.6%) from our previous prototype (±)-cis-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl) methanol (3) and the NSAIAs: acetyl salicylic acid, indomethacin, ibuprofen, ketoprofen, naproxen and diclofenac. The acetic acid-induced writhing method is able to determine that all investigated new hybrids showed stronger antinociceptive properties (2- to 10-fold less ED50 values) than their precursors. The highest antinociceptive effect was observed for compound 9 showing more than 10-fold less ED50 values than diclofenac and ninefold less ED50 value than compound 2. All compounds presented greater activity than the control group in the tail-flick test confirming the central antinociceptive effect. New hybrids did not alter the motor performance of mice by rota-rod performance and open-field tests. Investigated compounds 4-9 were not toxic after oral administration (LD50 >2000 mg/kg).
- Capim, Saulo L.,Goncalves, Gabriela M.,Dos Santos, Gabriela C.M.,Marinho, Bruno G.,Vasconcellos, Mario L.A.A.
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- Antiproliferative activity of Pt(IV) conjugates containing the non-steroidal anti-inflammatory drugs (NSAIDs) Ketoprofen and Naproxen
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Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antipr
- Ravera, Mauro,Zanellato, Ilaria,Gabano, Elisabetta,Perin, Elena,Rangone, Beatrice,Coppola, Marco,Osella, Domenico
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- (R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, New Chiral Auxiliaries for the Asymmetric Synthesis of α-Arylpropanoic Acids.
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Reaction of rac-α-arylpropanoyl chlorides with (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (R)- and (S)-1, in the presence of triethylamine, under standard esterification conditions, gave (R,R)- and (S,S)-3, respectively, with high diastereoselectivity.Controlled acidic hydrolysis afforded the corresponding (R)- or (S)-α-arylpropanoic acids with high enantioselectivity, the chiral auxiliary being recovered efficiently.
- Camps, Pelayo,Gimenez, Silvia
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- NO-NSAIDs. Part 3: Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs
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In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially "Safe NSAIDs," we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E2 (PGE2) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially "Safe NSAIDs" for the treatment of arthritic pain and inflammation.
- Borhade, Namdev,Pathan, Asif Rahimkhan,Halder, Somnath,Karwa, Manoj,Dhiman, Mini,Pamidiboina, Venu,Gund, Machhindra,Deshattiwar, Jagannath Janardhan,Mali, Sunil Vasantrao,Deshmukh, Nitin Janardanrao,Senthilkumar, Subrayan Palanisamy,Gaikwad, Parikshit,Tipparam, Santhosh Goud,Mudgal, Jayesh,Dutta, Milan Chandra,Burhan, Aslam Usmangani,Thakre, Gajanan,Sharma, Ankur,Deshpande, Shubhada,Desai, Dattatraya Chandrakant,Dubash, Nauzer Pervez,Jain, Arun Kumar,Sharma, Somesh,Nemmani, Kumar Venkata Subrahmanya,Satyam, Apparao
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- Novel penicillin analogues as potential antimicrobial agents; Design, synthesis and docking studies
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A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 ?. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents.
- Ashraf, Zaman,Bais, Abdul,Manir, Md. Maniruzzaman,Niazi, Umar
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Read Online
- New group of dexketoprofen trometamol new impurity and preparation method thereof
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The invention relates to a group of dexketoprofen trometamol new impurities, namely (S)-2 - (3 - benzoylphenyl) - N - (1, 3 -dihydroxy -2 - (hydroxymethyl) prop-2 -yl) propionamide. (S)-2 - ((S)-2 - (3 - Benzoylphenyl) propionamide) -3 - hydroxy -2 - (hyd
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Paragraph 0005
(2021/10/02)
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- The Effects of Prodrug Size and a Carbonyl Linker on l-Type Amino Acid Transporter 1-Targeted Cellular and Brain Uptake
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The l-type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l-DOPA) into the brain, and plays a role in cancer metabolism. Though there have been numerous reports of LAT1-targeted amino acid-drug conjugates (prodrugs), identifying the structural determinants to enhance substrate activity has been challenging. In this work, we investigated the position and orientation of a carbonyl group in linking hydrophobic moieties including the anti-inflammatory drug ketoprofen to l-tyrosine and l-phenylalanine. We found that esters of meta-carboxyl l-phenylalanine had better LAT1 transport rates than the corresponding acylated l-tyrosine analogues. However, as the size of the hydrophobic moiety increased, we observed a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition. Our results have important implications for designing amino acid prodrugs that target LAT1 at the blood-brain barrier or on cancer cells.
- Venteicher, Brooklynn,Merklin, Kasey,Ngo, Huy X.,Chien, Huan-Chieh,Hutchinson, Keino,Campbell, Jerome,Way, Hannah,Griffith, Joseph,Alvarado, Cesar,Chandra, Surabhi,Hill, Evan,Schlessinger, Avner,Thomas, Allen A.
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p. 869 - 880
(2020/12/15)
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- Pyrrolizine/indolizine-nsaid hybrids: Design, synthesis, biological evaluation, and molecular docking studies
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In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The ant
- Abdalla, Ashraf N.,Abourehab, Mohammed A. S.,Almalki, Faisal A.,Alqahtani, Alaa M.,Beshr, Eman A. M.,Gouda, Ahmed M.,Zaher, Dana M.
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- Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source
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Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via β-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.
- Kariofillis, Stavros K.,Shields, Benjamin J.,Tekle-Smith, Makeda A.,Zacuto, Michael J.,Doyle, Abigail G.
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supporting information
p. 7683 - 7689
(2020/04/22)
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- Visible-Light-Assisted Gold-Catalyzed Fluoroarylation of Allenoates
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A strategically novel synthetic method for the fluoroarylation of allenic ester was developed that enables the expedient construction of a host of β-fluoroalkyl-containing cinnamate derivatives. The reaction proceeds through visible-light-promoted gold redox catalysis, occurs smoothly under very mild reaction conditions, accommodates a large variety of functional groups, and more importantly allows the incorporation of fluorine and aryl groups with excellent regio- and stereoselectivity. The concomitant activation mode for both the allene motif and the hydrogen fluoride is key for the success of the reaction.
- Feng, Chao,Tang, Hai-Jun,Zhang, Xinggui,Zhang, Yu-Feng
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supporting information
p. 5242 - 5247
(2020/02/28)
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- Novel ketoprofen–antioxidants mutual codrugs as safer nonsteroidal anti-inflammatory drugs: Synthesis, kinetic and pharmacological evaluation
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Ketoprofen belongs to one of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs
- Sehajpal, Shikha,Prasad, Deo Nandan,Singh, Rajesh K.
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- Novel polyfunctional esters of ibuprofen and ketoprofen with hypolipidemic, lipoxygenase inhibitory and enhanced anti-inflammatory activity
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Abstract: A series of ibuprofen and ketoprofen esters were designed and synthesised, incorporating an antioxidant moiety, such as quercetin and salicylic alcohol, as well as anti-inflammatory or neuroprotective components. They showed greatly increased ac
- Theodosis-Nobelos, Panagiotis,Tziona, Paraskevi,Poptsis, Anastasios,Athanasekou, Chrysoula,Kourounakis, Panos N.,Rekka, Eleni A.
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p. 461 - 472
(2017/01/28)
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- COUPLING COMPOUNDS OF NSAID ANTI-INFLAMMATORY AND ANALGESIC DRUGS AND EGFR KINASE INHIBITORS, SYNTHESIS METHODS AND APPLICATIONS THEREOF
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The present invention discloses coupling compounds of a structure as shown in Formula I, II or III formed by connecting NSAID anti-inflammatory and analgesic drugs and EGFR inhibitors by ester bonds or pharmaceutically acceptable salts or stereoisomers thereof or prodrug molecules thereof: where R is a NSAID anti-inflammatory and analgesic drug. In the present invention, the coupling compounds obtained by coupling NSAID anti-inflammatory and analgesic drugs with EGFR inhibitors have excellent therapeutic effects of tumors and provide new drugs for clinic treatment options.
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Paragraph 0052
(2016/07/27)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of inflammation may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease, Ulcerative colitis, Crohn's disease, Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0112; 0121; 0122
(2015/06/03)
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- Pharmacological evaluation of isochromen-1-ones and their thioanalogues derived from anti-inflammatory drug ketoprofen
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The 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-one, 2 and their thio-analogues 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-thione, 3 and 3-{1-[3-(benzothioyl) phenyl]ethyl}-1H-isochromen-1-one, 5 were successfully obtained in good yield and purity from
- Napoleon, A. Arumugham,Bhagwat, Swati,Khan, Fazlur-Rahman Nawaz
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p. 1343 - 1351
(2013/07/11)
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- Mutual prodrugs containing bio-cleavable and drug releasable disulfide linkers
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We report herein the design and synthesis of several representative examples of novel mutual prodrugs containing nine distinct types of self-immolative drug-releasable disulfide linkers with urethane, ester, carbonate, or imide linkages between the linker and any two amine/amide/urea (primary or secondary) or carboxyl or hydroxyl (including phenolic)-containing drugs. We also report drug release profiles of a few representative mutual prodrugs in biological fluids such as simulated gastric fluid and human plasma. We also propose plausible mechanisms of drug release from these mutual prodrugs. We have also conducted a few mechanistic studies based on suggested sulfhydryl-assisted cleavage of mutual prodrugs and characterized a few important metabolites to give support to the proposed mechanism of drug release from the reported mutual prodrugs.
- Jain, Arun K.,Gund, Machhindra G.,Desai, Dattatraya C.,Borhade, Namdev,Senthilkumar, Subrayan P.,Dhiman, Mini,Mangu, Naveen K.,Mali, Sunil V.,Dubash, Nauzer P.,Halder, Somnath,Satyam, Apparao
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supporting information
p. 40 - 48
(2013/10/22)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
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The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of inflammation may he formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease. Ulcerative colitis, Crohn's disease. Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0094; 00103; 00104
(2013/12/03)
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- Compounds against inflammation and oxidative insult as potential agents for neurodegenerative disorders
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Amides of proline, a feature encountered in nootropics, via the carboxylic group of ibuprofen, indomethacin, ketoprofen and naproxen were prepared. Proline carboxylic group was amidated or esterified with potential antioxidant or neuroprotective compounds. Proline was replaced by 4-hydroxyproline, 2-pipecolic acid or omitted, for investigating the contribution of structure to activity. Anti-inflammatory activity was determined, and selected compounds were examined for anti-dyslipidemic action, protection against brain ischaemia/reperfusion and brain penetration. Springer Science+Business Media, LLC 2011.
- Doulgkeris, Christos M.,Siskou, Ioanna C.,Xanthopoulou, Nikoletta,Lagouri, Vassiliki,Kravaritou, Constantina,Eleftheriou, Phaedra,Kourounakis, Panos N.,Rekka, Eleni A.
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p. 2280 - 2291
(2012/11/07)
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- Synthesis, characterization and pharmacological evaluation of amino acid conjugates of ketoprofen
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Ketoprofen is used for its antipyretic, analgesic and antiinflammatory properties by inhibiting cyclooxygenase-1 and cyclooxygenase-2 enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors. Ketoprofen suffers from the general side effects of nonsteroidal antiinflammatory drugs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Different conjugates of ketoprofen have been synthesized by amidation with methyl esters of amino acids namely, phenylalanine, lysine, arginine, glycine, cysteine, valine, glutamine, serine, proline and alanine. Synthesized conjugates were characterized and evaluated for analgesic and antiinflammatory activities.
- Dubey,Jain,Bhadoria,Sinha
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experimental part
p. 1170 - 1174
(2012/08/28)
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- Synthesis and in vitro characterization of drug conjugates of l-carnitine as potential prodrugs that target human Octn2
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The objective was to evaluate the potential of drug conjugates with l-carnitine as prodrugs that target organic cation/carnitine transporter (OCTN2). Twenty-two l-carnitine analogues were evaluated for human organic cation/carnitine transporter (hOCTN2) inhibition; the 3'-hydroxyl group was found to be the only functional group not contributing to l-carnitine interaction with hOCTN2 among the three functional groups on l-carnitine (i.e., 3'-hydroxyl, amine, and carboxylate). The 3'-hydroxyl group on l-carnitine was therefore chosen as the conjugate site. Three drug-l-carnitine conjugates (i.e., valproyl-l-carnitine, naproxen-l-carnitine, and ketoprofen-l-carnitine) were synthesized along with two ketoprofen analogues that incorporated a linker group (glycolic acid or glycine) between ketoprofen and l-carnitine (i.e., ketoprofen-glycolic acid-l-carnitine and ketoprofen-glycine-l-carnitine). These potential prodrugs were evaluated for their in vitro inhibition, transport, and metabolism properties. All three drug-l-carnitine conjugates and ketoprofen-glycine-l-carnitine were OCTN2 inhibitors, as well as substrates. For valproyl-l-carnitine, Ki = 155± 19μM, Km = 132± 23μM, and normalized Jmax = 0.467± 0.028; for naproxen-l-carnitine, Ki = 5.97± 0.81μM, Km = 257± 57μM, and normalized Jmax = 0.141± 0.012; for ketoprofen-l-carnitine, Ki = 82.2± 5.3μM, Km = 77.0± 4.0μM, and normalized Jmax = 0.412± 0.015; for ketoprofen-glycine-l-carnitine, Ki = 14.4± 1.4μM, Km = 58.5± 8.7μM, and normalized Jmax = 0.0789± 0.0037. Ketoprofen-glycolic acid-l-carnitine was unstable in metabolic buffers and chemical buffers. On the contrary, naproxen-l-carnitine, ketoprofen-l-carnitine, and ketoprofen-glycine-l-carnitine were stable in chemical and metabolic buffers. The results demonstrate the potential of drug-l-carnitine conjugates to serve as prodrugs that target OCTN2.
- Diao, Lei,Polli, James E.
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experimental part
p. 3802 - 3816
(2012/06/30)
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- Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT
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The objective was to synthesize prodrugs of niacin and ketoprofen that target the human apical sodium-dependent bile acid transporter (ASBT) and potentially allow for prolonged drug release. Each drug was conjugated to the naturally occurring bile acid ch
- Zheng, Xiaowan,Polli, James E.
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experimental part
p. 111 - 118
(2012/01/13)
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- Cholesterol-diaryl ketone stereoisomeric dyads as models for "clean" type i and type II photooxygenation mechanisms
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Cholesterol (Ch) is a major target for oxidative degradation in cell membranes, a process which can occur by two mechanisms: Type I (via free radicals) and Type II (mediated by 1O2). In the present work, several dyads have been synthesized from β- and α-Ch and ketoprofen (KP) or tiaprofenic acid (TPA). Upon irradiation under anaerobic conditions, KP-α-Ch dyads were efficiently photolyzed, via intramolecular hydrogen abstraction from C-7. By contrast, KP-β-Ch, TPA-α-Ch, and TPA-β-Ch remained unchanged after prolonged irradiation. The transient absorption spectra of KP-α-Ch were assigned to the short-lived biradicals resulting from intramolecular hydrogen abstraction. Interestingly, the spectra and lifetimes obtained for the TPA-derived dyads were very similar to those of the TPA triplet excited state. For the KP-α-Ch dyads, generation of singlet oxygen was expectedly negligible. Conversely, for TPA-α-Ch a ΦΔ value as high as 0.5 was determined. Thus, KP-based dyads are appropriate models for clean type I Ch oxidation, whereas the TPA derivatives are suitable systems for investigation of the purely type II process. The Royal Society of Chemistry.
- Andreu, Inmaculada,Morera, Isabel M.,Bosca, Francisco,Sanchez, Laura,Camps, Pelayo,Miranda, Miguel A.
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supporting information; experimental part
p. 860 - 867
(2008/10/09)
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- Efficient and selective photogeneration of cholesterol-derived radicals by intramolecular hydrogen abstraction in model dyads
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Three model dyads have been synthesized by esterification of β- and α-cholesterol (Ch) with (S)- and/or (R)-ketoprofen (Kp). The α-dyads are efficient photogenerators of the 7-allyl Ch radicals by intramolecular H abstraction. Subsequent cyclization via C
- Andreu, Inmaculada,Bosca, Francisco,Sanchez, Laura,Morera, Isabel M.,Camps, Pelayo,Miranda, Miguel A.
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p. 4597 - 4600
(2007/10/03)
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- Synthesis of new chemical entities from paracetamol and NSAIDs with improved pharmacodynamic profile
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It was envisaged to combine high antipyretic activity of paracetamol into commonly used NSAIDs. To achieve this goal new chemical entities were synthesized by chemically combining paracetamol and NSAIDs, and biologically evaluated for their antipyretic, a
- Yadav, Mange Ram,Nimekar, Datta M.,Ananthakrishnan,Brahmkshatriya, Pathik S.,Shirude, Shrikant T.,Giridhar, Rajani,Parmar, Arvind,Balaraman
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p. 8701 - 8706
(2008/02/09)
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- New nuclear transcription factors regulators
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The present invention relates to novel compounds that are nuclear transcription factors (NTF) regulators. The present invention also provides methods for treating, preventing and/or reducing inflammation-associated diseases by regulating NTF in the cardiovascular, connective tissue, pulmonary, gastrointestinal, respiratory, urogenital, nervous, or cutaneous systems as well as tumoral and infective diseases employing said compounds. The present invention is based on the discovery that it is possible to link regulators of NTF to a pharmacologically active compound helpful for treating disorders in the cardiovascular, connective tissue, pulmonary, gastrointestinal, respiratory, urogenital, nervous, or cutaneous systems or tumoral and infective diseases. The resulting compounds have good bioavailability, increased activity and/or safety.
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Page/Page column 5
(2008/06/13)
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- Synthesis and biological testing of Acyl-CoA-ketoprofen conjugates as selective irreversible inhibitors of COX-2
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Ketoprofenoyl-CoA thioester 3 was synthesized by coupling ketoprofen to coenzyme A using the mixed anhydride method. Diastereoisomeric compounds 3a and 3b corresponding to the enantiomers of ketoprofen, were obtained in optically pure form by preparative
- Levoin, Nicolas,Chrétien, Fran?oise,Lapicque, Fran?oise,Chapleur, Yves
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p. 753 - 757
(2007/10/03)
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- Synthesis of a new insoluble polymer-supported chiral alcohol auxiliary and its first application to nucleophilic addition to ketenes
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The preparation of a new optically active alcohol with a carboxylic function that allowed its attachment to an amine-functionalized insoluble polymer is described. Its first use as a polymer supported chiral auxiliary is demonstrated by asymmetric transformation of two racemic aryl propionic acids via ketene formation (95-96% ee).
- Akkari,Calmes,Mai,Rolland,Martinez
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p. 5859 - 5865
(2007/10/03)
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- Prodrugs: Part 3. 2-Formylphenyl esters of indomethacin, ketoprofen and ibuprofen and 6-substituted 2-formyl and 2-acylphenyl esters of aspirin
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The synthesis and study of a novel series of potential prodrugs of indomethacin, ketoprofen, ibuprofen and aspirin are reported. 2-Formylphenyl esters of the NSAIDs, together with two 6-substituted 2-formyl and two 2-acylphenyl aspirins and 4-formylphenyl indomethacin, have been prepared. A study of their alkaline and neutral hydrolysis shows that these compounds, with the exception of 2-acetylphenyl aspirin, act as true prodrugs of the NSAIDs, giving the NSAID and acylphenol. The rates of hydrolysis and activation parameters indicate that the 2-acylphenyl esters employ an intramolecular catalytic route. The 2-formylphenyl esters were more potent as anti-inflammatory agents than the parent compounds in the carragheenan-induced paw oedema test.
- Abordo, Evelyn A.,Bowden, Keith,Huntington, Anthony P.,Powell, Sarah L.
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- Dynamic enzymatic resolution of thioesters
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A detailed investigation of several issues related to the enzymatic resolution of thioesters under conditions of continuous racemization of substrate was conducted. The kinetic acidity of the α-protons of a series of α-substituted propionate thioesters was studied. It was found that the rate of α-proton exchange could be enhanced as much as 20-fold by variation of the thiol moiety, increasing the range of compounds to which enzymatic dynamic resolution may be applied. The relative rates of hydrolysis of ethyl butyrate and ethyl thiobutyrate by several enzymes commonly used in enzymatic resolution were determined. All of the enzymes studied exhibited similar rates of thioester and oxoester hydrolysis except for the esterase from pig liver, which showed very low activity in thioester hydrolysis. Dynamic resolution of the propargyl and trifluoroethyl thioesters of α- phenylpropionate was conducted using subtilisin Carlsberg as a catalyst. These examples demonstrated that enzymatic dynamic resolution can be applied even when the rate of α-proton exchange and the enantioselectivity of the enzyme are fairly low. A dynamic enzymatic transesterification procedure was demonstrated in the resolution of the trifluoroethyl thioester of α-(2,4- dichlorophenoxy)propionate, and product was obtained in 93% ee. This work helps expand and define the scope of enzymatic dynamic resolution of thioesters.
- Um, Pil-Je,Drueckhammer, Dale G.
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p. 5605 - 5610
(2007/10/03)
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- Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs
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Nonsteroidal antiinflammatory drugs which have been substituted with a nitrogen monoxide group; compositions comprising (i) a nonsteroidal antiinflammatory drug, which can optionally be substituted with a nitrogen monoxide group and (ii) a compound that directly donates, transfers or releases a nitrogen monoxide group (preferably as a charged species, particularly nitrosonium); and methods of treatment of inflammation, pain, gastrointestinal lesions and/or fever using the compositions are disclosed. The compounds and compositions protect against the gastrointestinal, renal and other toxicities that are otherwise induced by nonsteroidal antiinflammatory drugs.
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- Asymmetric synthesis of ketoprofen: a surprising base catalyst effect during asymmetric addition of pantolactone to methyl (3-benzoylphenyl) ketene
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The best diastereoselectivity of addition of a chiral alcohol to the ketene derived from ketoprofen was obtained with R or S pantolactone (ed=99percent).Depending on the tertiary amine used both for ketene formation and as catalyst during addition, the diastereoisomeric ratio of esters could be strongly modified and even inverted.Mild saponification afforded R or S ketoprofen in enantiomeric excess of up to 99percent.
- Calmes, Monique,Daunis, Jacques,Jacquier, Robert,Natt, Francois
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p. 6875 - 6880
(2007/10/02)
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- Derivatives of Substituted Propionic Acid as Antiinflammatory Agents
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N-Acetyl-p-aminophenol derivatives of d-naproxen (IVa), ibuprofen (IVb) and ketoprofen (IVc) have been synthesised.Some acetylated β-D-glucopyranosides (Va-c) of ketoprofen, aspirin, and diclofenac have also been prepared and their antiinflammatory activi
- Singh, Pritpal,Hingorani, L. L.,Trivedi, G. K.
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p. 498 - 500
(2007/10/02)
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- Bulky amine analogues of ketoprofen: Potent antiinflammatory agents
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Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay on rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substituent (Cl or F) on the terminal aromatic ring. Removal of the α-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
- Schlegel,Zenitz,Fellows,Laskowski,Behn,Phillips,Botton,Speight
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p. 1682 - 1690
(2007/10/02)
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