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.
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.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Debenham
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Madsen-Duggan
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Clements
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Walsh
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kuethe
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Reibarkh
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Salowe
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sonatore
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Milligan
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Visco
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stickens
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Wolff
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Pang
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Randy R
authors.initials: RR
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
mesh_terms: D000284:Administration, Oral; D000740:Anemia / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C000620531:N-(bis(4-methoxyphenyl)methyl)-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide; D011724:Pyridazines; D011743:Pyrimidines; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases