Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

The design and discovery
of a new series
of (5-alkynyl-3-hydroxypicolinoyl)­glycine inhibitors of prolyl hydroxylase
(PHD) are described. These compounds showed potent in vitro inhibitory
activity toward PHD2 in a fluorescence polarization-based assay. Remarkably,
oral administration of 17, with an IC50 of
64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin
(EPO), and alleviate anemia in a cisplatin-induced anemia mouse model
with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities
of 55.7 and 54.0%, respectively, and shows excellent safety profiles
even at a high dose of 200 mg/kg in these animals. Based on these
results, 17 is currently being evaluated in a phase I
clinical trial for anemia.