Discovery of DS28120313 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4,6-disubstituted indazole derivatives

  • Bioorg Med Chem Lett. 2017 Dec 1;27(23):5252-5257. doi: 10.1016/j.bmcl.2017.10.031.
Takeshi Fukuda  1 ,  Riki Goto  2 ,  Toshihiro Kiho  3 ,  Kenjiro Ueda  4 ,  Sumie Muramatsu  4 ,  Masami Hashimoto  4 ,  Anri Aki  2 ,  Kengo Watanabe  5 ,  Naoki Tanaka  6
Affiliations
  • 1. Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3. Modality Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4. Pain & Neuroscience Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 6. Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 29079471 DOI: 10.1016/j.bmcl.2017.10.031
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 inhibitor 1 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.

Keywords
Anemia of chronic disease; Hepcidin; Indazole; Kinase; Pyrazole.
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