Abstract

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients with a variety of underlying pathologies such as chronic kidney disease (CKD). Treatment with recombinant human EPO (rHuEPO) at supraphysiological concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients and presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF)1α and HIF2α control the physiological response to hypoxia and invoke a program of increased erythropoeisis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs) which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiological erythropoietic response, presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863, a pyrimidinetrione-glycinamide inhibitor, designed to mimic the binding of N-oxalylglycine to the PHDs. GSK1278863, a low nanomolar inhibitor of PHDs 1-3, stabilizes HIFα 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 pre-clinical species following 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 CKD.