Potent Triazolopyridine Myeloperoxidase Inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• Myeloperoxidase (MPO) produces reactive oxygen species implicated in chronic inflammatory diseases.
• Existing MPO inhibitors require optimization for acid stability and specificity.

Purpose of the Study:

• To optimize a triazolopyrimidine MPO inhibitor for enhanced acid stability and to eliminate methyl guanine methyl transferase (MGMT) activity.
• To explore synthetic routes for rapid optimization of MPO inhibitors.
• To guide rational drug design through structural analysis of MPO-inhibitor complexes.

Main Methods:

• Chemical synthesis and optimization of triazolopyrimidine derivatives.
• Exploration of various synthetic routes, focusing on benzyl ether side chain modification.
• X-ray crystallography to determine the binding modes of inhibitors in the MPO active site.
• In vivo testing of MPO inhibition in an acute mouse inflammation model.

Main Results:

• Successfully optimized MPO inhibitors with improved acid stability and no MGMT activity.
• Identified key structural features influencing MPO inhibition through crystal structures.
• Thioether 36 demonstrated significant MPO inhibition in a mouse model following oral administration.

Conclusions:

• The optimized MPO inhibitors exhibit promising properties for treating inflammatory conditions.
• Rational drug design, guided by structural insights, is effective for developing potent and selective MPO inhibitors.
• Compound 36 represents a potential therapeutic candidate for managing acute inflammation.