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

[Display omitted] •Hepcidin, a peptide hormone, is a master regulator of systemic iron mobilizations (83 characters).•Hepcidin inhibition could be a strategy for treating anemia of chronic disease (80 characters).•4-Aminopyrimidine compound was founded as a hit of Hepcidin production inhibitor (82 characters).•Optimization study led to a potent and bioavailable Hepcidin production inhibitor (83 characters).•DS42450411 showed serum Hepcidin-lowering effects in an acute inflammation model (82 characters). 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.