Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 6: ADME Properties of Drugs

Li Di

Edward H. Kerns

Wyeth Research, Princeton, New Jersey

ADME properties have tremendous impact on the success of drug candidates. They are a set of fundamental physico-chemical and biochemical properties of drug molecules that can be affected by physiologic conditions in vivo: solubility, permeability, stability, metabolism, and others. ADME properties can be improved through structural modification by medicinal chemists. They are important both in vitro and in vivo. A successful drug must possess a balance of good potency and drug-like properties. High-throughput ADME assays have been developed and implemented widely in the pharmaceutical industry to reduce the attrition of drug candidates. The data are used to identify potential liabilities, guide structural modification, prioritize lead series, select compounds for in vivo studies, and diagnose in vivo assay results. Studies have demonstrated that early screening of ADME properties is a successful approach to enhance the quality of drug candidates.

Drug discovery typically starts from an unmet medical need [1], followed by target identification–validation, HTS (high-throughput screening) and hit finding, as well as hit-to-lead and lead optimization (Fig. 6.1). Once an active compound is identified, preclinical development starts. If the compound is efficacious and safe in animals, it will be evaluated in human clinical trials after an IND (investigational new drug) is filed. Phase I clinical ...