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

Takeshi Fukuda; Takashi Ishiyama; Takahiro Katagiri; Kenjiro Ueda; Sumie Muramatsu; Masami Hashimoto; Anri Aki; Daichi Baba; Kengo Watanabe; Naoki Tanaka

doi:10.1016/j.bmcl.2018.09.010

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. Epub 2018 Sep 8.

Authors

Affiliations

¹ Rare Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: fukuda.takeshi.zv@daiichisankyo.co.jp.
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.

MeSH terms

Administration, Oral
Aminopyridines / administration & dosage
Aminopyridines / chemical synthesis
Aminopyridines / pharmacokinetics
Aminopyridines / pharmacology*
Anemia / drug therapy*
Anemia / etiology
Animals
Binding Sites
Cell Line, Tumor
Drug Design
Hepcidins / antagonists & inhibitors*
Hepcidins / blood
Hepcidins / chemistry
Humans
Inflammation / chemically induced
Inflammation / complications
Interleukin-6 / metabolism
Iron / metabolism
Male
Mice, Inbred C57BL
Molecular Structure
Quinazolines / administration & dosage
Quinazolines / chemical synthesis
Quinazolines / pharmacokinetics
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Aminopyridines
Hepcidins
Interleukin-6
Quinazolines
Iron