Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction

J Med Chem. 2022 Sep 8;65(17):11485-11496. doi: 10.1021/acs.jmedchem.1c02141. Epub 2022 Aug 25.


Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC50, 1.5 nM in vitro) and selectivity (>450-fold vs thyroid peroxidase in vitro), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2b/3 efficacy study of AZD4831 in patients with HFpEF started in 2021.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Heart Failure* / drug therapy
  • Humans
  • Iodide Peroxidase / therapeutic use
  • Peroxidase
  • Pyrimidines
  • Pyrroles
  • Stroke Volume / physiology


  • AZD4831
  • Pyrimidines
  • Pyrroles
  • Peroxidase
  • Iodide Peroxidase