Discovery of DS79182026: A potent orally active hepcidin production inhibitor

  • Bioorg Med Chem Lett. 2017 Aug 15;27(16):3716-3722. doi: 10.1016/j.bmcl.2017.07.004.
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: 28705644 DOI: 10.1016/j.bmcl.2017.07.004
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 benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

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