Cell permeability beyond the rule of 5

Area of Science:

• Medicinal Chemistry
• Pharmacokinetics
• Drug Discovery

Background:

• Drug discovery targeting large, flat binding sites often requires compounds beyond the traditional
• rule of 5
• (bRo5) criteria.
• These bRo5 compounds present pharmacokinetic challenges, including poor solubility, permeability, and increased efflux and metabolism.
• Recent successes indicate that orally bioavailable and cell-permeable drugs can be developed from bRo5 chemical space.

Purpose of the Study:

• To explore strategies for developing cell-permeable and orally bioavailable drugs from bRo5 chemical space.
• To investigate the role of conformational flexibility in achieving favorable pharmacokinetic properties for bRo5 compounds.
• To assess the impact of transporter-mediated effects on drug absorption and efflux in the bRo5 space.

Main Methods:

• Review of recent drug approvals and studies involving bRo5 compounds.
• Analysis of tactics used to enhance cell permeability, such as N-methylation and intramolecular hydrogen bonds.
• Evaluation of computational conformational analysis in predicting cell permeability.
• Examination of transporter-mediated efflux and absorption mechanisms for bRo5 drugs.

Main Results:

• Tactics like shielding polarity can improve permeability but may reduce solubility.
• Conformationally flexible compounds demonstrate potential for high permeability and solubility, crucial for oral absorption.
• Transporter-mediated efflux is common for bRo5 drugs but often manageable with high oral doses.
• Limited data exists on transporter-mediated intestinal absorption for bRo5 drugs.

Conclusions:

• Developing orally bioavailable drugs beyond the
• rule of 5
• is feasible, with conformational flexibility being a key design element.
• Further research is needed to understand the fundamental properties governing transporter interactions for bRo5 drugs.
• Computational methods can aid in designing bRo5 compounds with improved pharmacokinetic profiles.