Discovery and ADMET: Where Are We Now

Dennis      A. Smith

Abstract

The gradual alignment with all of drug metabolism with all aspects of drug discovery and development has led to a complete realignment of the way the work is conducted. From a background of conducting bespoke in vivo studies much of the work is now in a high throughput screening mode. Large technological advances have been made, but the nature of drug metabolism processes, being multi-system and promiscuous means that much of the help provided to the medicinal chemistry is reactive rather than based on fundamental disposition structure-activity relationships. Lessons learned around the chemical and physicochemical properties more often associated with succesfull discovery and development projects are only moderately helpful when the high value pharmacological targets of today only yield potent ligands outside of the boundaries these properties describe. Pivotal to the impact of these properties is the intrinsic permeability of a molecule, something not as widely recognised as perhaps it should be. Metabolic lability is still a problem and the tactics employed are unchanged in 20 years: attempt to lower lipophilicity, if it is too high overall or introduce blocking groups, particularly halogens, after identifying the sites of metabolism Perhaps the greatest success drug metabolism science has had over the last fifteen years is its pivotal role in characterising drug-drug interactions and providing screening systems and computational models to investigate them. It still has many undeveloped areas of the science such as the role of metabolites in drug activity and why compounds vary in their extent of biliary excretion.

Keywords: Screening, CYP450, transporters, permeability, bile, metabolites, physicochemistry

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