Discovery of Novel and Potent Prolyl Hydroxylase Domain-Containing Protein (PHD) Inhibitors for The Treatment of Anemia

Stabilization
of hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase
domain enzymes (PHDs) represents a breakthrough in treating anemia
associated with chronic kidney disease. Here, we identified a novel
scaffold for noncarboxylic PHD inhibitors by utilizing structure-based
drug design (SBDD) and generative models. Iterative optimization of
potency and solubility resulted in compound 15 which
potently inhibits PHD thus stabilizing HIF-α in vitro. X-ray cocrystal structure confirmed the binding model was distinct
from previously reported carboxylic acid PHD inhibitors by pushing
away the R383 and Y303 residues resulting in a larger inner subpocket.
Furthermore, compound 15 demonstrated a favorable in vitro/in vivo absorption, distribution,
metabolism, and excretion (ADME) profile, low drug–drug interaction
risk, and clean early safety profiling. Functionally, oral administration
of compound 15 at 10 mg/kg every day (QD) mitigated anemia
in a 5/6 nephrectomy rat disease model.