Myeloperoxidase (MPO) is a heme-containing enzyme found in neutrophilic granulocytes (neutrophils) and monocytes. Systemic levels of MPO is a well-described risk factor for various cardiovascular diseases and it is believed that pharmacological inhibition of MPO activity could attenuate cardiac fibrosis and preserve cardiac function under conditions that may trigger (diastolic) HFpEF and (systolic) HFrEF. AZD4831 is oxidized selectively by MPO, binds covalently to, and irreversibly inactivates the enzyme. We describe the discovery of AZD4831, with emphasis on increasing the selectivity margin to thyroidperoxidase (TPO) and reducing the therapeutic dose. Furthermore, we report our approach to exploring safety and dose prediction for a covalent inhibitor and how these preclinical assessments translated in the Phase 1 SAD and MAD studies. AZD4831 is currently in Ph 2 clinical development in patients suffering from HFpEF.

Discovery of AZD4831, a mechanism-based irreversible inhibitor of myeloperoxidase, as a potential treatment for heart failure with preserved ejection fraction

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.