Assay Service for assessing ADME properties and in vivo PK properties with the selected vendor.

1. The Section on Medicinal Chemistry (SMC) develops new molecular entities with implications in improving health and treatment for various metabolic and alcohol associated diseases. To assess the translational potential of novel molecular entities, which would allow us to make decisions to proceed with the compounds for further development we utilize multiple derisking assays. These assays comprise of both cell-based (in vitro) testing and then eventually in mice to assess pharmacokinetic parameters to see if the drug is orally available.

Request to procure Chemical Reagent (Assay) Development & Laboratory Testing Service SMC to produce grouped ADME assays and perform a Pharmacokinetic study in C57BL6 mice. By including the Caco-2 Permeability Assay in our ADME evaluation it'll accurately predict the oral absorption potential of our compounds. This well-established in vitro model closely mimics the human intestinal epithelium, providing critical insights into a compound’s passive diffusion, active transport, and efflux processes, such as those mediated by P-glycoprotein (P-gp). The data generated from this assay are vital for informing structure-activity relationship (SAR) optimization, improving compound permeability, and reducing transporter-related liabilities that could hinder bioavailability. CACO and MDCKR assays allow to know the brain penetrance of the compounds. hERG assays allow to know if the compounds will show cardiac toxicity. The plasma stability and binding show how the compounds behave in bodily fluids. Finally, the best compounds then undergo testing in mice to know if they can be given orally and thus have translational potential in human testing. These assays are integral to the work of section on medicinal chemistry at NIAAA as these enable to progress compounds for further development as therapeutics in metabolic and alcohol use disorders.