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Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Sep 08; Vol. 65 (17), pp. 11485-11496. Date of Electronic Publication: 2022 Aug 25. - Publication Year :
- 2022
-
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 <subscript>50</subscript> , 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.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36005476
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c02141