Pyridine and pyridinone-based factor XIa inhibitors

Area of Science:

• Medicinal Chemistry
• Structural Biology

Background:

• The imidazole ring is a common scaffold in drug discovery.
• Understanding structure-activity relationships (SAR) is crucial for developing new therapeutics.

Purpose of the Study:

• To investigate six-membered ring replacements for the imidazole scaffold.
• To identify novel potent and selective inhibitors of factor XIa.

Main Methods:

• Synthesis of pyridine and pyridinone analogs.
• Structure-activity relationship (SAR) studies.
• X-ray crystallography to determine binding modes.

Main Results:

• Discovery of potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors.
• Detailed SAR data comparing six-membered rings to imidazole.
• X-ray crystal structures revealed key differences in binding interactions.

Conclusions:

• Six-membered ring replacements offer a viable alternative to imidazole scaffolds for factor XIa inhibitors.
• Understanding SAR and structural differences guides the design of more effective inhibitors.