Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 363; no. 3; pp. 336 - 347
• Main Authors: Ariazi, Jennifer L, Duffy, Kevin J, Adams, David F, Fitch, Duke M, Luo, Lusong, Pappalardi, Melissa, Biju, Mangatt, DiFilippo, Erin Hugger, Shaw, Tony, Wiggall, Ken, Erickson-Miller, Connie
• Format: Journal Article
• Language: English
• Published: United States 01.12.2017
• Subjects: Animals; Barbiturates - administration & dosage; Barbiturates - adverse effects; Barbiturates - pharmacokinetics; Barbiturates - pharmacology; Basic Helix-Loop-Helix Transcription Factors - agonists; Basic Helix-Loop-Helix Transcription Factors - chemistry; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Drugs, Investigational - administration & dosage; Drugs, Investigational - adverse effects; Drugs, Investigational - pharmacokinetics; Drugs, Investigational - pharmacology; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Erythropoiesis - drug effects; Erythropoietin - agonists; Erythropoietin - genetics; Erythropoietin - metabolism; Female; Glycine - administration & dosage; Glycine - adverse effects; Glycine - analogs & derivatives; Glycine - pharmacokinetics; Glycine - pharmacology; Hematinics - administration & dosage; Hematinics - adverse effects; Hematinics - pharmacokinetics; Hematinics - pharmacology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - agonists; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Mice; Protein Stability - drug effects; Rats, Sprague-Dawley; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Toxicity Tests, Chronic
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.117.242503

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1 and HIF2 control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIF are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIF for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIF in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.