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

• Published in: Journal of medicinal chemistry 2022-09, Vol.65 (17), p.11485-11496
• Main Authors: Inghardt, Tord, Antonsson, Thomas, Ericsson, Cecilia, Hovdal, Daniel, Johannesson, Petra, Johansson, Carina, Jurva, Ulrik, Kajanus, Johan, Kull, Bengt, Michaëlsson, Erik, Pettersen, Anna, Sjögren, Tove, Sörensen, Henrik, Westerlund, Kristina, Lindstedt, Eva-Lotte
• Format: Article
• Language: English
• Subjects: Drug Annotation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c02141

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.