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ID: ALA4765235
Journal: J Med Chem
Title: Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia.
Authors: Debenham JS,Madsen-Duggan C,Clements MJ,Walsh TF,Kuethe JT,Reibarkh M,Salowe SP,Sonatore LM,Hajdu R,Milligan JA,Visco DM,Zhou D,Lingham RB,Stickens D,DeMartino JA,Tong X,Wolff M,Pang J,Miller RR,Sherer EC,Hale JJ
Abstract: The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.
CiteXplore: 28002958