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

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.

• Authors: Takeshi Fukuda, Takashi Ishiyama, Takahiro Katagiri, Kenjiro Ueda, Sumie Muramatsu, Masami Hashimoto, Anri Aki, Daichi Baba, Kengo Watanabe, Naoki Tanaka
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 20 Pg. 3333-3337 (11 01 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 30217414 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Aminopyridines
• Hepcidins
• Interleukin-6
• Quinazolines
• Iron

Topics

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