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.

中文翻译：

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DS42450411作为有效的口服活性铁调素生产抑制剂的发现：新型4-氨基嘧啶衍生物的设计和优化

铁调素已成为系统性铁稳态中的主要调节分子。抑制铁调素可能是治疗慢性疾病性贫血的有利策略。在这里，我们报道了一系列4-氨基嘧啶化合物作为铁调素生产的抑制剂的设计，合成和结构-活性关系（SAR）。对1的优化研究导致设计出一种有效且可生物利用的铁调素抑制剂34（DS42450411），该抑制剂在白介素6诱导的急性炎症小鼠模型中显示出降低铁调素的作用。