Discovery of DS79182026: A potent orally active hepcidin production inhibitor

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

doi:10.1016/j.bmcl.2017.07.004

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. Epub 2017 Jul 3.

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: 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.

MeSH terms

Administration, Oral
Animals
Benzoxazoles / administration & dosage
Benzoxazoles / chemistry*
Benzoxazoles / pharmacokinetics
Benzoxazoles / pharmacology*
Carbamates / administration & dosage
Carbamates / chemistry*
Carbamates / pharmacokinetics
Carbamates / pharmacology*
Gene Expression Regulation / drug effects
Half-Life
Hepcidins / antagonists & inhibitors*
Hepcidins / genetics
Hepcidins / metabolism
Inflammation / chemically induced
Inflammation / drug therapy
Inhibitory Concentration 50
Interleukin-6
Maleates / administration & dosage
Maleates / chemistry
Maleates / pharmacokinetics
Maleates / pharmacology
Mice
Mice, Inbred C57BL
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Models, Animal
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
RNA, Messenger / metabolism
Structure-Activity Relationship

Substances

Benzoxazoles
Carbamates
DS79182026
Hepcidins
Interleukin-6
Maleates
Protein Kinase Inhibitors
RNA, Messenger
benzmalecene