Macrocyclization: Enhancing Drug-like Properties of Discoidin Domain Receptor Kinase Inhibitors

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Pharmacology

Background:

• Discoidin domain receptor (DDR) inhibitors are explored for treating fibrotic diseases.
• Linear inhibitors face challenges in drug-like properties.
• Macrocyclization is a strategy to develop novel ligands for challenging targets.

Purpose of the Study:

• To design macrocyclic inhibitors as alternatives to a linear DDR inhibitor (1).
• To enhance the drug-like profile of inhibitor 1 using molecular docking and chameleonicity.
• To synthesize and evaluate matched pairs of macrocycles with varying flexibility and linker features.

Main Methods:

• Molecular docking and chameleonicity considerations in drug design.
• Synthesis of macrocyclic compounds and matched pairs.
• Physicochemical characterization including solubility, permeability, and lipophilicity analysis.

Main Results:

• Compound 5a, a macrocyclic inhibitor, demonstrated nanomolar activity.
• Significant improvements in solubility and permeability were observed for compound 5a.
• Lipophilicity, not polarity, was identified as a key driver of permeability for the macrocycles.

Conclusions:

• Macrocyclization is effective in developing DDR inhibitors with improved drug-like properties.
• Compound 5a represents a promising lead for fibrotic disease treatment.
• Traditional 2D descriptors have limitations in predicting macrocycle ADME properties.