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Updated: Nov 10, 2025
Fast and Specific Assessment of the Halogenating Peroxidase Activity in Leukocyte-enriched Blood Samples
Published on: July 28, 2016
Small molecule and macrocyclic pyrazole derived inhibitors of myeloperoxidase (MPO)
Carol H Hu1, Meriah W Neissel Valente1, O Scott Halpern1
1Research and Development, Bristol-Myers Squibb Company, P. O. Box 5400, Princeton, NJ 08543, United States.
Abstract:
Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC50 value of 2.4 μM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.
Insights
Researchers designed novel myeloperoxidase (MPO) inhibitors for cardiovascular disease treatment. Compound 30, a potent macrocyclic MPO inhibitor, demonstrated significant selectivity against thyroid peroxidase (TPO).
Area of Science:
- Medicinal Chemistry
- Enzyme Inhibition
- Cardiovascular Pharmacology
Background:
- Myeloperoxidase (MPO) is an enzyme crucial for antimicrobial defense.
- MPO is implicated in the pathogenesis of chronic inflammatory conditions, including coronary artery disease.
Purpose of the Study:
- To design and evaluate novel inhibitors of myeloperoxidase (MPO) for potential cardiovascular disease treatment.
- To explore structure-activity relationships (SAR) for MPO inhibition using substituted pyrazoles and macrocyclic structures.
Main Methods:
- Utilized the crystal structure of MPO and triazolopyridine 3 for structure-based inhibitor design.
- Synthesized novel inhibitors incorporating substituted pyrazoles to target active site hydrophobic and hydrophilic regions.
- Optimized alkylation chemistry and macrocyclization strategies to develop potent MPO inhibitors.
Main Results:
- Identified piperidine 17, inhibiting HOCl production from neutrophils with an IC50 of 2.4 μM and showing selectivity over thyroid peroxidase (TPO).
- Developed potent macrocyclic MPO inhibitors, such as compound 30, through optimized synthesis and macrocyclization.
- Achieved significant MPO inhibition with selectivity against TPO in optimized analogs.
Conclusions:
- Novel substituted pyrazole and macrocyclic compounds effectively inhibit myeloperoxidase (MPO) activity.
- The developed inhibitors show promise for treating MPO-related chronic inflammatory diseases, particularly cardiovascular conditions.
- Compound 30 represents a potent and selective MPO inhibitor with therapeutic potential.
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