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

John S Debenham; Christina Madsen-Duggan; Matthew J Clements; Thomas F Walsh; Jeffrey T Kuethe; Mikhail Reibarkh; Scott P Salowe; Lisa M Sonatore; Richard Hajdu; James A Milligan; Denise M Visco; Dan Zhou; Russell B Lingham; Dominique Stickens; Julie A DeMartino; Xinchun Tong; Michael Wolff; Jianmei Pang; Randy R Miller; Edward C Sherer; Jeffrey J Hale

doi:10.1021/acs.jmedchem.6b01242

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. Epub 2016 Nov 30.

Authors

John S Debenham¹, Christina Madsen-Duggan¹, Matthew J Clements¹, Thomas F Walsh¹, Jeffrey T Kuethe¹, Mikhail Reibarkh¹, Scott P Salowe¹, Lisa M Sonatore¹, Richard Hajdu¹, James A Milligan¹, Denise M Visco¹, Dan Zhou¹, Russell B Lingham¹, Dominique Stickens¹, Julie A DeMartino¹, Xinchun Tong¹, Michael Wolff¹, Jianmei Pang¹, Randy R Miller¹, Edward C Sherer¹, Jeffrey J Hale¹

Affiliation

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Enzyme Inhibitors
N-(bis(4-methoxyphenyl)methyl)-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide
Pyridazines
Pyrimidines
Hypoxia-Inducible Factor-Proline Dioxygenases