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

## TL;DR

Researchers designed macrocyclic DDR kinase inhibitors with better drug properties, including improved solubility and permeability.

## Contribution

The study introduces macrocyclic DDR kinase inhibitors with enhanced drug-like properties through innovative design strategies.

## Key findings

- Compound 5a showed nanomolar activity and improved solubility and permeability.
- Lipophilicity, not polarity, was found to drive permeability in macrocycle pairs.
- Traditional 2D computational descriptors failed to predict macrocycle ADME properties.

## Abstract

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.