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

ABSTRACT: 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

SUBMITTER: Inghardt T 

PROVIDER: S-EPMC9469207 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature