title: Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors.
abstract: Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
authors.affiliation: Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: fukuda.takeshi.zv@daiichisankyo.co.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Pain & Neuroscience Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishiyama
authors.affiliation: Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Riki
authors.initials: R
authors.lastname: Goto
authors.affiliation: Pain & Neuroscience Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Muramatsu
authors.affiliation: Pain & Neuroscience Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000740:Anemia / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002908:Chronic Disease; D006207:Half-Life; D064451:Hepcidins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D007191:Indazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D015850:Interleukin-6 / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D064451:Hepcidins; D007191:Indazoles; D015850:Interleukin-6
keywords: Anemia of chronic disease; Hepcidin; Indazole; Intraperitoneal administration; Phenol