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.
Keywords:
Aminopyrimidine; Anemia of chronic disease; DYRK1a; Hepcidin.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Aminopyridines / administration & dosage
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Aminopyridines / chemical synthesis
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Aminopyridines / pharmacokinetics
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Aminopyridines / pharmacology*
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Anemia / drug therapy*
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Anemia / etiology
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Animals
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Binding Sites
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Cell Line, Tumor
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Drug Design
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Hepcidins / antagonists & inhibitors*
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Hepcidins / blood
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Hepcidins / chemistry
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Humans
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Inflammation / chemically induced
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Inflammation / complications
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Interleukin-6 / metabolism
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Iron / metabolism
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Male
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Mice, Inbred C57BL
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Molecular Structure
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Quinazolines / administration & dosage
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Quinazolines / chemical synthesis
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Quinazolines / pharmacokinetics
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Quinazolines / pharmacology*
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Structure-Activity Relationship
Substances
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Aminopyridines
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Hepcidins
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Interleukin-6
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Quinazolines
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Iron