- Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey
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1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were ev
- Paulson,Zhang,Jessen,Lawal,Liu,Dudkowski,Wang,Chang,Yang,Findlay,Berge,Markos,Breau,Hribar,Yuan
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- Synthesis of spirosuccinimidesviaannulative cyclization betweenN-aryl indazolols and maleimides under rhodium(iii) catalysis
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The rhodium(iii)-catalyzed spiroannulation reaction betweenN-aryl indazol-3-ols and maleimides is described herein. The developed method is showcased by the construction of spirosuccinimides using bioactive molecule-linked and chemical probe-linked maleim
- Kang, Ju Young,An, Won,Kim, Suho,Kwon, Na Yeon,Jeong, Taejoo,Ghosh, Prithwish,Kim, Hyung Sik,Mishra, Neeraj Kumar,Kim, In Su
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p. 10947 - 10950
(2021/10/22)
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- Synthesis of Benzylic Alcohols by C-H Oxidation
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Selective methylene C-H oxidation for the synthesis of alcohols with a broad scope and functional group tolerance is challenging due to the high proclivity for further oxidation of alcohols to ketones. Here, we report the selective synthesis of benzylic alcohols employing bis(methanesulfonyl) peroxide as an oxidant. We attempt to provide a rationale for the selectivity for monooxygenation, which is distinct from previous work; a proton-coupled electron transfer mechanism (PCET) may account for the difference in reactivity. We envision that our method will be useful for applications in the discovery of drugs and agrochemicals.
- Tanwar, Lalita,B?rgel, Jonas,Ritter, Tobias
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p. 17983 - 17988
(2019/11/14)
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- Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its methanesulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies
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A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs 12a-b) wherein an O2-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, O2-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the bromomethyl group of 5-(4-bromomethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (9a), and its methanesulfonyl analog (9b), were synthesized. The diazen-1-ium-1,2-diolate compounds 12a-b released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (6.1-8.2% range). In comparison, the percentage NO released was significantly higher (76-77% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs 12a-b were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (10a), and its methanesulfonyl analog (10b), would be released from the parent NONO-coxib 12a or 12b upon in vivo cleavage by non-specific serum esterases. The hydroxymethyl compounds 10a-b were weak inhibitors of the cyclooxygenase-1 (COX-1) and COX-2 isozymes (IC50 = 3.7-10.5 μM range). However, the hydroxymethyl compounds 10a-b and the parent NONO-coxibs 12a-b exhibited good AI activities (ED50 = 76.7-111.6 μmol/kg po range) that were greater than that exhibited by the reference drugs aspirin (ED50 = 710 μmol/kg po) and ibuprofen (ED50 = 327 μmol/kg po), but less than that of celecoxib (ED50 = 30.9 μmol/kg po). These studies indicate hybrid ester AI/NO-donor prodrugs (NONO-coxibs) constitutes a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects.
- Abdellatif, Khaled R.A.,Chowdhury, Morshed Alam,Dong, Ying,Velazquez, Carlos,Das, Dipankar,Suresh, Mavanur R.,Knaus, Edward E.
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experimental part
p. 9694 - 9698
(2009/04/07)
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- Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies
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A method of using pyrazolyl benzenesulfonamide compounds in treating inflammation and inflammation-related disorders in companion animals is disclosed.
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- Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
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A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II: STR1 or a pharmaceutically-acceptable salt thereof.
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- Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)- 3(trifluoromethyl)-1h-pyrazol-1-yl]benzenesulfonamide (sc-58635, celecoxib)
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A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC- 236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-y1]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
- Penning, Thomas D.,Talley, John J.,Bertenshaw, Stephen R.,Carter, Jeffery S.,Collins, Paul W.,Docter, Stephen,Graneto, Matthew J.,Lee, Len F.,Malecha, James W.,Miyashiro, Julie M.,Rogers, Roland S.,Rogier,Yu, Stella S.,Anderson, Gary D.,Burton, Earl G.,Cogburn, J. Nita,Gregory, Susan A.,Koboldt, Carol M.,Perkins, William E.,Seibert, Karen,Veenhuizen, Amy W.,Zhang, Yan Y.,Isakson, Peter C.
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p. 1347 - 1365
(2007/10/03)
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- Substituted pyrazolyl benzenesulfonamide for the treatment of inflammation
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A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I: STR1
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- SUBSTITUTED PYRAZOLYL BENZENESULFONAMIDES
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A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I: or a pharmaceutically-acceptable salt thereof
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