Macrocycles in Drug Discovery─Learning from the Past for the Future

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Macrocyclic drugs are predominantly utilized in oncology and infectious diseases.
• Natural products are a rich source, contributing 80-90% of macrocyclic drugs and clinical candidates.
• Many macrocycles target challenging binding sites, often existing beyond traditional 'Rule of 5' parameters.

Purpose of the Study:

• To analyze FDA-approved macrocyclic drugs, clinical candidates, and literature to understand their role in drug discovery.
• To identify key characteristics and trends in macrocycle utilization.
• To explore predictive models for oral bioavailability of macrocyclic compounds.

Main Methods:

• Analysis of FDA-approved macrocyclic drugs and clinical candidates.
• Literature review of recent macrocycle research.
• Evaluation of chemical properties and target binding sites.
• Development and application of bi-descriptor models (HBD, MW, cLogP) to predict oral bioavailability.

Main Results:

• Oncology is the primary focus for macrocyclic clinical candidates and research literature.
• Natural products significantly influence the structural complexity and origin of macrocyclic drugs.
• Despite often exceeding 'Rule of 5' properties, 30-40% of macrocycles demonstrate oral bioavailability.
• Simple models effectively differentiate oral from parenteral macrocycles, serving as useful design filters.

Conclusions:

• Macrocycles remain crucial in drug discovery, particularly for complex targets and indications like oncology.
• Leveraging natural product scaffolds and advanced conformational analysis can drive innovation in de novo macrocycle design.
• Predictive models offer practical tools for optimizing macrocycle properties, including oral absorption.