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

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.