title: Novel acid-type cyclooxygenase-2 inhibitors: Design, synthesis, and structure-activity relationship for anti-inflammatory drug.
abstract: Cyclooxygenase (COX) is a key rate-limiting enzyme for prostaglandin (PG) production cascades in the human body. The mechanisms of both the anti-inflammation effects and the side-effects of traditional COX inhibitors are associated with the existence of two COX isoforms. Thus while COX-1 is predominantly expressed ubiquitously and constitutively, and it serves a housekeeping role in processes such as gastrointestinal (GI) mucosa protection, COX-2 is absent or exhibits a low level of expression in most tissues, and is highly upregulated in response to endotoxin, virus, inflammatory or tissue-injury stimuli/signals, and tumour promoter in the various types of organs, tissues, and cells. Furthermore, COX-2 contribution to PGE(2) and PGI(2) production evokes and sustains systemic or peripheral inflammatory disease, but it is not involved in the COX-1-mediated GI tract events. Also, hypersensitivity of aspirin owing to its inhibitory action against COX-1 is a significant concern clinically. Consequently, highly selective COX-2 inhibitors have been needed for the treatment of inflammatory- and inflammation related-diseases that include pyrexia, inflammation, pain, rheumatoid arthritis, osteoarthritis, and cancers. In this study, a series of novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5- or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid analogues was designed, synthesized, and evaluated to identify potent and selective COX-2 inhibitors as potential agents against inflammatory diseases. As significant findings, the present study clarified unique structure-activity relationship of the analogues toward potent and selective COX-2 inhibition in vitro, and identified 2-{6-fluoro-2-[4-methyl-2-pridinyl)carbonyl]-1H-indol-3-yl}acetic acid as a potent and selective COX-2 inhibitor in vitro that demonstrated orally potent anti-inflammation efficacy against carrageenan-induced oedema formation in the foot of SPF/VAF male SD rats as a peripheral inflammation model in vivo.
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. Shigeo_Hayashi@nifty.com
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hayashi
authors.forename: Naomi
authors.initials: N
authors.lastname: Ueno
authors.forename: Akio
authors.initials: A
authors.lastname: Murase
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Junji
authors.initials: J
authors.lastname: Takada
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D002351:Carrageenan; D051546:Cyclooxygenase 2