A Novel Selective Prostaglandin E 2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats
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ORIGINAL ARTICLE
A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats Ryusuke Sugita,1 Harumi Kuwabara,2 Kotaro Sugimoto,2 Kazufumi Kubota,3 Yuichiro Imamura,4 Toshihiro Kiho,5 Atsushi Tengeiji,6 Katsuhiro Kawakami,7 and Kohei Shimada2,8
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, antiinflammatory drugs (NSAIDs) or COX-2-selective inhibitors. KEY WORDS: prostaglandin E2; arthritis; pyrexia; NSAIDs.
INTRODUCTION Conventional NSAIDs are widely used in the treatment of rheumatoid arthritis, osteoarthritis, and 1
Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan 2 Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan 3 Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan 4 Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan 5 Medical Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan 6 Venture Science Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan 7 Global Project Management Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan 8 To whom correspondence should be addressed at Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa R&D Center, 1-258, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. E-mail: [email protected]
inflammatory pain. Traditional NSAIDs inhibit both COX-1 and COX-2 activities, and COX-1 inhibition causes adverse effects on the gastrointestinal (GI) tract [1]. Therefore, COX-2-selective inhibitors have been expected to be an alternative to traditional NSAIDs with fewer adverse effects on the GI tract [2, 3]. Several COX-2-selective inhibitors, including celecoxib, rofecoxib, and valdecoxib, have appeared on the market. As expected, all have shown similar analgesic effects with a reduced risk of GI injury compared to traditional NSAIDs [4–6]. However, rofecoxib was revealed to be related to
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