In Vitro Structure−Activity Relationship and in Vivo Studies for a Novel Class of Cyclooxygenase-2 Inhibitors: 5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone Derivatives
| Autor: | Ki Wha Lee, Jin Kwan Kim, Young Im Oh, Jin Kyu Choi, Kyung Min Lim, Joo Hyun Moh, Hyun Ju Koh, Young Hoon Choi, Minsoo Noh, Jiyoung Kim, Youngjoo Byun, Yeon Su Jeong, Song Seok Shin, Young Ho Park, Shin Chung |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Male Models Molecular Stereochemistry In Vitro Techniques Carrageenan Chemical synthesis Sulfone Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery Animals Edema Humans Structure–activity relationship Cyclooxygenase Inhibitors Stomach Ulcer Furans IC50 Cyclooxygenase 2 Inhibitors biology Chemistry Membrane Proteins Arthritis Experimental In vitro Rats Isoenzymes Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Enzyme inhibitor Cyclooxygenase 1 Macrophages Peritoneal biology.protein Molecular Medicine Cyclooxygenase |
| Zdroj: | Journal of Medicinal Chemistry. 47:792-804 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm020545z |
| Popis: | 5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles. |
| Databáze: | OpenAIRE |
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