Discovery of DS28120313 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4, 6-disubstituted indazole derivatives. Issue 23 (1st December 2017)

• Record Type: Journal Article
• Authors: Fukuda, Takeshi; Goto, Riki; Kiho, Toshihiro; Ueda, Kenjiro; Muramatsu, Sumie; Hashimoto, Masami; Aki, Anri; Watanabe, Kengo; Tanaka, Naoki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 23(2017)
• Page Start: 5252
• Page End: 5257
• Publication Date: 2017-12-01
• Subjects: Hepcidin -- Anemia of chronic disease -- Indazole -- Pyrazole -- Kinase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.10.031
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure–activity relationships (SAR) of a series of 4, 6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.