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

  • J Med Chem. 2022 Sep 8;65(17):11485-11496. doi: 10.1021/acs.jmedchem.1c02141.
Tord Inghardt  1 ,  Thomas Antonsson  1 ,  Cecilia Ericsson  1 ,  Daniel Hovdal  1 ,  Petra Johannesson  1 ,  Carina Johansson  2 ,  Ulrik Jurva  1 ,  Johan Kajanus  1 ,  Bengt Kull  1 ,  Erik Michaëlsson  1 ,  Anna Pettersen  3 ,  Tove Sjögren  2 ,  Henrik Sörensen  1 ,  Kristina Westerlund  1 ,  Eva-Lotte Lindstedt  1
Affiliations
  • 1. Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 50 Mölndal, Gothenburg, Sweden.
  • 2. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 50 Mölndal, Gothenburg, Sweden.
  • 3. Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 50 Mölndal, Gothenburg, Sweden.
PMID: 36005476 DOI: 10.1021/acs.jmedchem.1c02141
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 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.

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