The Missing Link(er): A Roadmap to Macrocyclization in Drug Discovery

Abstract

Macrocycles are one of nature's preferred choices to generate large but cell-permeable bioactive molecules. Macrocyclization is increasingly prominent in medicinal chemistry beyond natural products, especially for difficult-to-drug targets. However, strategies to best exploit the potential of macrocycles are only beginning to emerge. Here we survey drug discovery campaigns from the past decade that cumulated in advanced macrocyclic drug-like compounds or drug candidates. Most macrocycles were conceived by ring closing based on U-or C-shaped bioactive conformations observed in co-crystal structures. We focus on the key step from linear precursors to the first macrocycle and the follow-up optimization of the resulting macrocyclic scaffold. Conformational control recurrently emerged as a key factor for macrocycle properties and linkers as an opportunity for optimization. With increasingly challenging drug targets, we expect these trends to become more prominent and relevant. ■ SIGNIFICANCE • Summary of illustrative examples of how linear molecules can be converted into macrocycles. • Direct comparison of linear and macrocyclic ligands and their properties and analysis of underlying molecular driving forces. • Structure-based analysis of the key transition points from linear lead compounds to macrocycles in contemporary drug discovery programs. • Analysis and guidelines for linker design as an important area for the optimization of macrocycles.