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

Takeshi Fukuda; Riki Goto; Toshihiro Kiho; Kenjiro Ueda; Sumie Muramatsu; Masami Hashimoto; Anri Aki; Kengo Watanabe; Naoki Tanaka

doi:10.1016/j.bmcl.2017.10.031

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. Epub 2017 Oct 16.

Authors

Takeshi Fukuda¹, Riki Goto², Toshihiro Kiho³, Kenjiro Ueda⁴, Sumie Muramatsu⁴, Masami Hashimoto⁴, Anri Aki², Kengo Watanabe⁵, Naoki Tanaka⁶

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.

MeSH terms

Acute Lung Injury / chemically induced
Acute Lung Injury / drug therapy*
Administration, Oral
Animals
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery*
Hep G2 Cells
Hepcidins / antagonists & inhibitors*
Hepcidins / biosynthesis
Humans
Indazoles / administration & dosage
Indazoles / chemistry
Indazoles / pharmacology*
Inflammation / chemically induced
Inflammation / drug therapy*
Interleukin-6
Mice
Molecular Structure
Pyrazoles / administration & dosage
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

DS28120313
Hepcidins
Indazoles
Interleukin-6
Pyrazoles