Intestinal absorption screening of mixtures from combinatorial libraries in the Caco-2 model

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Drug Delivery

Background:

• Understanding intestinal transport is crucial for developing orally available drugs.
• N-substituted glycine (NSG) peptoids offer a diverse chemical space for drug discovery.
• The Caco-2 cell model mimics intestinal absorption for in vitro studies.

Purpose of the Study:

• To evaluate arbitrary mixtures of NSG peptoids in the Caco-2 model to accelerate structure-transport relationship studies.
• To assess the influence of common structural elements within mixtures on intestinal absorption.
• To identify compounds with favorable oral bioavailability characteristics.

Main Methods:

• Six mixtures of NSG peptoids (24 compounds) were analyzed using High-Performance Liquid Chromatography (HPLC).
• Aggregate apparent permeability coefficients (Papp) were calculated by summing peak areas.
• Mass spectrometry identified the chemical structures of compounds that permeated the Caco-2 cells.

Main Results:

• Linear trimeric NSG peptoid mixtures showed very low permeability (Papp < 0.8 x 10(-6) cm/sec), indicating poor absorption.
• Dimeric NSG peptoid mixtures exhibited higher aggregate Papp values, ranging from 6.9 x 10(-6) to 14 x 10(-6) cm/sec.
• Transported compounds from dimeric mixtures appeared to cross the Caco-2 barrier via passive diffusion.

Conclusions:

• Mixtures can be effectively utilized to study structure-transport relationships in the Caco-2 model.
• This methodology aids in the rational design of future chemical libraries for oral drug discovery.
• The study highlights novel applications of chemical mixtures within the Caco-2 assay system.