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

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 sho...

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Veröffentlicht in:	Journal of medicinal chemistry 2016-12, Vol.59 (24), p.11039-11049
Hauptverfasser:	Debenham, John S, Madsen-Duggan, Christina, Clements, Matthew J, Walsh, Thomas F, Kuethe, Jeffrey T, Reibarkh, Mikhail, Salowe, Scott P, Sonatore, Lisa M, Hajdu, Richard, Milligan, James A, Visco, Denise M, Zhou, Dan, Lingham, Russell B, Stickens, Dominique, DeMartino, Julie A, Tong, Xinchun, Wolff, Michael, Pang, Jianmei, Miller, Randy R, Sherer, Edward C, Hale, Jeffrey J
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Anemia - drug therapy Anemia - enzymology Animals Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism Mice Mice, Inbred C57BL Models, Molecular Molecular Structure Pyridazines - administration & dosage Pyridazines - chemistry Pyridazines - pharmacology Pyrimidines - administration & dosage Pyrimidines - chemistry Pyrimidines - pharmacology Rats Rats, Sprague-Dawley Structure-Activity Relationship
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