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

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.