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

  • J Med Chem. 2016 Dec 22;59(24):11039-11049. doi: 10.1021/acs.jmedchem.6b01242.
John S Debenham  1 ,  Christina Madsen-Duggan  1 ,  Matthew J Clements  1 ,  Thomas F Walsh  1 ,  Jeffrey T Kuethe  1 ,  Mikhail Reibarkh  1 ,  Scott P Salowe  1 ,  Lisa M Sonatore  1 ,  Richard Hajdu  1 ,  James A Milligan  1 ,  Denise M Visco  1 ,  Dan Zhou  1 ,  Russell B Lingham  1 ,  Dominique Stickens  1 ,  Julie A DeMartino  1 ,  Xinchun Tong  1 ,  Michael Wolff  1 ,  Jianmei Pang  1 ,  Randy R Miller  1 ,  Edward C Sherer  1 ,  Jeffrey J Hale  1
Affiliations
  • 1. Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
PMID: 28002958 DOI: 10.1021/acs.jmedchem.6b01242
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.

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