title: A novel selective prostaglandin E2 synthesis inhibitor relieves pyrexia and arthritis in Guinea pigs inflammatory models.
abstract: Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Sugita
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tachida
authors.affiliation: Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibayama
authors.affiliation: Medical Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kiho
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., Tokyo, Japan. Electronic address: shimada.kohei.ma@daiichisankyo.co.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shimada
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy*; D052160:Benzothiazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003864:Depression, Chemical; D015232:Dinoprostone / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever / Q000188:drug therapy*; D006168:Guinea Pigs; D007093:Imidazoles / Q000627:therapeutic use; D007213:Indomethacin / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D008264:Macrophages / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D010437:Peptic Ulcer / Q000188:drug therapy; D010616:Phenanthrenes / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013268:Stimulation, Chemical; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: C000612844:1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-(2-(hydroxymethyl)cyclohexyl)piperidine-4-carboxamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052160:Benzothiazoles; D007093:Imidazoles; C526699:MF63 compound; D010616:Phenanthrenes; D010880:Piperidines; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone; D007213:Indomethacin
keywords: Arthritis; Inflammation; Inflammatory pain; Prostaglandin E(2); Pyrexia