title: 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.
abstract: 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.
authors.affiliation: Drug Discovery, AmorePacific R&D Center, 314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-729, South Korea.
authors.forename: Song Seok
authors.initials: SS
authors.lastname: Shin
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Lim
authors.forename: Jin Kyu
authors.initials: JK
authors.lastname: Choi
authors.forename: Ki-Wha
authors.initials: KW
authors.lastname: Lee
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Moh
authors.forename: Jin Kwan
authors.initials: JK
authors.lastname: Kim
authors.forename: Yeon Su
authors.initials: YS
authors.lastname: Jeong
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Choi
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Koh
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Young Im
authors.initials: YI
authors.lastname: Oh
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Noh
authors.forename: Shin
authors.initials: S
authors.lastname: Chung
mesh_terms: D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D008565:Membrane Proteins; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat