title: A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats.
abstract: Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Sugita
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kuwabara
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Medical Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kiho
authors.affiliation: Venture Science Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tengeiji
authors.affiliation: Global Project Management Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. shimada.kohei.ma@daiichisankyo.co.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shimada
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D058633:Antipyretics / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D058633:Antipyretics; D008070:Lipopolysaccharides; C000613322:N-(3-carbamoylcyclohexyl)-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide; D010880:Piperidines; D011804:Quinolines; C000601854:piperidine-4-carboxamide; D015232:Dinoprostone
keywords: NSAIDs; arthritis; prostaglandin E2; pyrexia