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 (IC 50 , 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 2 b /3 efficacy study of AZD4831 in patients with HFpEF started in 2021.

Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque

“…Long-term human studies with MPO inhibitors have not been carried out to date. In phase I studies, once-daily single, and multiple ascending dosing of AZD4831 (a 2-thioxanthine-based MPO inhibitor like AZM198) in healthy volunteers was generally well tolerated [ 20 ]. From a clinical perspective, most patients with MPO deficiency are asymptomatic, with severe (candida) infectious complications occurring only occasionally in the setting of comorbid diabetes mellitus.…”

“…We observed that in that model, MPO activity was higher in unstable than stable plaque, and that genetic or pharmacological blockade of MPO activity attenuated the formation of unstable plaque [ 18 ]. Importantly, the MPO suicide inhibitor used (AZM198) [ 19 , 20 ] decreased plaque MPO activity and plaque instability without affecting circulating leukocytes and lipids, lesion macrophages, MPO protein and lipids [ 18 ]. These findings raise the possibility of stabilizing vulnerable plaque via the therapeutic inhibition of arterial MPO activity.…”

Application of Accelerator Mass Spectrometry to Characterize the Mass Balance Recovery and Disposition of AZD4831, a Novel Myeloperoxidase Inhibitor, following Administration of an Oral Radiolabeled Microtracer Dose in Humans

“…Radiolabeled 14 C-AZD4831 (Fig. 1) was manufactured by Pharmaron (Rushden, UK) following the procedure described previously (Inghardt et al, 2022). The solid material was isolated following crystallization from ethanol and water.…”

“…AZD4831 -(R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1Hpyrrolo [3,2-d]pyrimidin-4(5H)-one -is a novel, covalent MPO inhibitor with high selectivity for MPO at low oral doses (Inghardt et al, 2022). In Phase I studies in healthy volunteers, AZD4831 was rapidly absorbed with a long plasma half-life, This article has not been copyedited and formatted.…”

Protective Effects of Therapeutic Neutrophil Depletion and Myeloperoxidase Inhibition on Left Ventricular Function and Remodeling in Myocardial Infarction

“…Thioxanthines are a class of suicide substrates that irreversibly inactivate MPO through modification of its heme groups and thereby inhibit HOCl production [20]. They have already passed phase I clinical trials and are currently being investigated in phase II studies in HF with preserved ejection fraction (NCT03756285) [21,22]. Further preclinical studies have shown beneficial effects of MPO inhibition on atherosclerotic plaque stability and pulmonary vascular function [23][24][25].…”