Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives

  • Bioorg Med Chem Lett. 2018 Nov 1;28(20):3333-3337. doi: 10.1016/j.bmcl.2018.09.010.
Takeshi Fukuda  1 ,  Takashi Ishiyama  2 ,  Takahiro Katagiri  2 ,  Kenjiro Ueda  3 ,  Sumie Muramatsu  3 ,  Masami Hashimoto  4 ,  Anri Aki  5 ,  Daichi Baba  6 ,  Kengo Watanabe  7 ,  Naoki Tanaka  8
Affiliations
  • 1. Rare Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. Rare Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3. Pain & Neuroscience Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4. Medical Information Department, Daiichi Sankyo Co., Ltd, 3-5-1 Nihombashihoncyo, Chuo-ku, Tokyo 103-8426, Japan.
  • 5. Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 6. Post-Marketing Regulatory Affairs Department, Daiichi Sankyo Co., Ltd, 3-5-1 Nihombashihoncyo, Chuo-ku, Tokyo 103-8426, Japan.
  • 7. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 8. Oncology Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 30217414 DOI: 10.1016/j.bmcl.2018.09.010
Abstract

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.

Keywords
Aminopyrimidine; Anemia of chronic disease; DYRK1a; Hepcidin.
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