Abstract
Provided herein are novel myeloperoxidase inhibitors, pharmaceutical compositions, use of such compounds in treating inflammatory, cardiovascular, respiratory, renal, hepatic, and neurological diseases, cancer, and neutrophilic-driven diseases, and processes for preparing such compounds.
Important Compound Classes
Title
Inhibitors of Myeloperoxidase
Patent Publication Number
WO 2024/038131 A1
Publication Date
February 22, 2024
Priority Application
US 63/398,939
Priority Date
August 18, 2022
Inventors
Inghardt, T.; Lindstedt, E.-L.; Jurva, U.; Selmi, N.
Assignee Company
AstraZeneca AB, Sweden
Disease Area
Inflammatory, cardiovascular, respiratory, renal, hepatic, and neurological diseases, cancer, and neutrophilic-driven diseases
Biological Target
Myeloperoxidase
Summary
Myeloperoxidase (MPO) is a heme-containing enzyme primarily expressed in neutrophilic granulocytes (neutrophils). MPO is one member of a diverse protein family of mammalian peroxidases that also includes eosinophil peroxidase (EPX), lactoperoxidase (LPO), thyroid peroxidase (TPO), and others. MPO is activated by hydrogen peroxide, the source of which can be superoxide dismutase (SOD)-catalyzed NADPH-derived superoxide anion and xanthine oxidase-derived superoxide anion and hydrogen peroxide formed upon purine oxidation.
By numbers, neutrophils are the dominating leukocyte population, representing a highly dynamic cellular population that is part of the first line of defense toward stressors, be they microbial or sterile triggers. Within neutrophils, preformed MPO is stored at millimolar concentration in granules, which fuse the phagosomes containing the engulfed microbial prey, causing activation of MPO and killing the microbe.
The present application describes a series of novel MPO inhibitors for the treatment of inflammatory, cardiovascular, respiratory, renal, hepatic, and neurological diseases, cancer, and neutrophilic-driven diseases. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
X = CH or N; Y1 = CZ1 or N; Y2 = CZ2 or N; Y3 = CZ3 or N; Y4 = CZ4 or N; and Y5 = CZ5 or N.
Key Structures
Biological Assay
The MPO enzymatic assay was performed. The compounds described in this application were tested for their ability to inhibit MPO. The MPO IC50 values (μM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for MPO inhibition and the biological data
obtained from testing representative examples.
Claims
Total claims: 78
Compound claims: 69
Pharmaceutical composition claims: 2
Method of treatment claims: 7
Recent Review Articles
The author declares no competing financial interest.
References
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