| Autor: |
Julie A. DeMartino, James A. Milligan, Edward C. Sherer, Thomas F. Walsh, Richard Hajdu, Russell B. Lingham, Xinchun Tong, Michael Wolff, Denise M. Visco, Mikhail Reibarkh, Matthew J. Clements, Jeffrey T. Kuethe, Randy R. Miller, Christina B. Madsen-Duggan, Lisa M. Sonatore, Scott P. Salowe, Dominique Stickens, Jianmei Pang, Jeffrey J. Hale, Dan Zhou, John S. Debenham |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 59(24) |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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