Scaffold hopping strategy to derive 4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b']dipyridine-3-carb onylglycine derivatives as a novel hypoxia-inducible factor prolyl hydroxylase domain inhibitor for the potential treatment of chronic kidney disease anemia

Derivatives of 4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b & PRIME;]dipyridine-3-carbonylglycine were developed as a novel hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibitor. The chemical space of the tricyclic 4-hydroxypyridinyl glycines was examined thoroughly during our optimization study. One of our most potent compounds 12ar exhibits superior enzymatic activity to the known PHD inhibitors that are in the late stage of clinical studies. The functional efficacy of our PHD inhibitors was confirmed via the increased level of erythropoietin (EPO) expression in a dose-dependent manner in vitro.