The hypoxia inducible factor prolyl hydroxylase domain (HIF-PHD) enzymes are oxygen-dependent hydroxylases that normally function to downregulate the HIF-family of heterodimeric transcription factors which, in turn, regulate the physiological response to hypoxia. HIF-PHD inhibitors can be thought of as "hypoxia-mimetics" with regard to erythropoiesis, leading not only to the induction of erythropoietin (EPO) but also to the natural mobilization and utilization of iron stores, thereby offering an additional advantage over erythropoiesis stimulating agents (ESAs, typically recombinant human EPO) by reducing or eliminating the need for iron supplementation. A safe and effective oral agent capable of increasing erythropoietin levels and positively affecting hematological parameters has the potential to revolutionize anemia treatment. Proof-of-concept for the mechanism of HIF-PHD inhibition for the treatment of anemia in CKD patients has been established. However, MRL profiling of HIF-PHD inhibitors in pre-clinical species has revealed undesirable pleiotropic effects associated with systemic HIF-PHD inhibition. We reasoned that a liver-targeting strategy exploiting uptake by organic anion transporter proteins may mitigate these systemic effects. We describe details of a chemical design strategy which resulted in structurally diverse, liver-selective, inhibitors of HIF-PHD enzymes. Oral administration of these compounds gave rise to a liver-driven increase in EPO with no effect on key extra-hepatic endpoints, thereby establishing pre-clinical validation for our strategy.

Liver targeted HIF-PHD inhibitors for the treatment of anemia

249th National Meeting (2015)

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