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

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Macrocycles are prevalent in nature for creating large, cell-permeable bioactive molecules.
• Macrocyclization is a growing strategy in medicinal chemistry, particularly for targeting proteins previously considered undruggable.
• Current strategies for macrocycle exploitation in drug discovery are still evolving.

Purpose of the Study:

• To survey drug discovery campaigns from the last decade that resulted in advanced macrocyclic drug candidates.
• To analyze the key steps and optimization strategies in macrocyclic drug development.
• To identify recurring trends and opportunities in macrocycle-based drug design.

Main Methods:

• Review of drug discovery campaigns focusing on macrocyclic compounds.
• Analysis of macrocyclization strategies, including ring-closing based on conformational data.
• Examination of optimization processes for macrocyclic scaffolds and linkers.

Main Results:

• Most macrocycles were designed using U- or C-shaped conformations from co-crystal structures.
• The transition from linear precursors to macrocycles and subsequent scaffold optimization were critical steps.
• Conformational control was consistently identified as a crucial factor influencing macrocycle properties.
• Linker selection presented a significant opportunity for optimizing macrocyclic compounds.

Conclusions:

• Macrocyclization is a vital approach for developing drug-like molecules against challenging targets.
• Conformational control and strategic linker design are key to successful macrocyclic drug development.
• The trends observed are expected to gain further importance as drug discovery tackles increasingly complex targets.