Property-Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Passive membrane permeability is a critical hurdle in developing orally available macrocyclic drugs.
• Current strategies often involve N-methylation or D-amino acid incorporation, with limitations.
• Novel approaches are needed to enhance macrocycle bioavailability.

Purpose of the Study:

• To investigate the impact of incorporating heterocyclic grafts, specifically azole rings, into macrocycles.
• To assess the effects of iterative amino acid substitution with heterocycles on macrocycle properties.
• To explore the structure-property relationships governing passive membrane permeability in modified macrocycles.

Main Methods:

• Systematic replacement of amino acid residues with azole heterocycles in a macrocyclic framework.
• Evaluation of lipophilicity and Parallel Artificial Membrane Permeability Assay (PAMPA) for permeability assessment.
• Nuclear Magnetic Resonance (NMR) spectroscopy and molecular dynamics (MD) simulations to analyze structural changes.

Main Results:

• Stepwise substitution of amino acids with heterocycles significantly enhanced macrocycle lipophilicity and PAMPA permeability.
• The improvement in permeability did not exhibit a linear correlation with the number of incorporated heterocycles.
• NMR and MD simulations revealed specific structural consequences of heterocycle incorporation, influencing conformation.

Conclusions:

• Heterocyclic grafting is a viable strategy to substantially improve passive membrane permeability of macrocycles.
• The non-linear relationship highlights the complex interplay between macrocycle conformation and permeability.
• These novel heterocyclic macrocyclic scaffolds offer promising potential for future drug discovery efforts.