Lead Generation for a HIF Prolyl Hydroxylase Inhibitor: Discovery of (7-Hydroxy-[1,2,4]triazolo[1,5‑]pyridine-8-carbonyl)glycine as a Lead Compound of Enarodustat.

Lead generation is a crucial process in drug discovery, and the identification of druglike lead compounds is essential to increase the chances of success in this field. Orally available hypoxia-inducible factor prolyl hydroxylase inhibitors have been a new treatment for renal anemia in chronic kidney disease patients. In our journey to enarodustat, approved in Japan, China, and South Korea, we adopted a pharmacophore-based scaffold-hopping strategy from binding mode analysis of known inhibitors. During the search for lead compounds, cell permeability was found to be a key factor in cell activity. Therefore, membrane permeability, ligand efficiency, and lipophilic ligand efficiency were utilized as compasses for the lead generation. We successfully identified compound bearing a [1,2,4]-triazolo-[4,3-]-pyridine core as a lead compound. Structures of enarodustat and compound differed only by the presence or absence of a phenethyl group, implying that the identification of a high-quality lead compound led to our success.