Renal anemia develops in the early stages of chronic kidney disease (CKD) and increases in frequency as the disease deteriorates. The primary cause is thought to be a decrease in erythropoietin (EPO) due to renal dysfunction. Erythropoietin-stimulating agents (ESAs), such as recombinant human erythropoietin (rhEPO), darbepoetin beta, and epoetin beta pegol, have been classically used to treat renal anemia. Hypoxia inducible factor (HIF) is a key transcription factor that plays a central role in the response to hypoxia. In such situations, HIF induces various genes related to erythropoiesis including EPO. Levels of HIF are regulated metabolically via hydroxylation of HIF at a proline residue by the HIF prolyl hydroxylase (HIF-PH). This mechanism suggests that inhibition of HIF-PH might increase endogenous EPO levels as a result of HIF stabilization and could serve as an alternative to ESAs. Indeed, several orally available HIF-PH inhibitors have been approved, providing new treatment options for CKD patients.
In this study, we present our efforts on the lead generation and optimization of enarodustut, which was approved in Japan and China. Our journey to enarodustat began with a pharmacophore-based scaffold hopping strategy from binding mode analysis of known inhibitors at the lead generation stage. During the search for lead compounds, cell permeability was found to be a key factor in cell activity. Therefore, membrane permeability (P_app), ligand efficiency (LE) and lipophilic ligand efficiency (LLE) were utilized as the compasses for lead generation. As a result, we succeeded in identifying compound A bearing an [1,2,4]triazolo[4,3-a]pyridine core as a lead compound. Lead optimization to improve the efficacy of EPO release in cells and in vivo by improving cell permeability led to the discovery of enarodustat, with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats.

Masahiro Yokota

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