title: Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept.
abstract: Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.
authors.affiliation: Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasumi
authors.affiliation: Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Saito
authors.affiliation: Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Kato
authors.affiliation: Pharmacokinetics Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shirota
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Sato
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, 4-3, 3-Chome, Sakae-cho, Hamura-shi, Tokyo 205-8501, Japan. Electronic address: ohta-s@aska-pharma.co.jp.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000600872:AKP-001; D007555:Isoxazoles; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Antedrug; IBD; Isoxazole; p38 MAP kinase