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

Macrocyclization, a well-established strategy for developing ligands against challenging drug targets, was employed to design macrocyclic alternatives to a linear discoidin domain receptor (DDR) inhibitor (1) with potential applications in treating fibrotic diseases. This study aimed to enhance the drug-like profile of 1 through innovative design strategies encompassing molecular docking and chameleonicity considerations. These efforts resulted in the synthesis of matched pairs of macrocycles differing in flexibility and linker features. Compound 5a emerged as a promising lead, exhibiting nanomolar-range activity, significantly improved solubility, and excellent permeability. Comprehensive experimental physicochemical characterization further highlighted the modest impact of ionization, the major role played by lipophilicity (but not polarity) in driving permeability of the investigated matched pairs, and the limitations of traditional 2D computational descriptors in predicting macrocycle ADME-related properties.