title: Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested. In contrast, we have found that the NSAID rofecoxib has very weak membrane permeabilizing activity. To understand the membrane permeabilizing activity of coxibs in terms of their structure-activity relationship, we separated the structures of celecoxib and rofecoxib into three parts, synthesized hybrid compounds by substitution of each of the parts, and examined the membrane permeabilizing activities of these hybrids. The results suggest that the sulfonamidophenyl subgroup of celecoxib or the methanesulfonylphenyl subgroup of rofecoxib is important for their potent or weak membrane permeabilizing activity, respectively. These findings provide important information for design and synthesis of new coxibs with lower membrane permeabilizing activity.
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan; Shujitsu University School of Pharmacy, Okayama 703-8516, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamakawa
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Katsu
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hanaya
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan. Electronic address: mizushima-th@pha.keio.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008051:Lipid Bilayers; D008081:Liposomes; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib
keywords: COX-2 selectivity; Celecoxib; Gastric adverse effect; Membrane permeabilization; Rofecoxib