Drug targeting and retrometabolic drug design approaches Introduction

Abstract Traditional methods for drug design have relied on optimization of drug activity with little regard for drug safety. Such manipulation often produces highly potent derivatives with equally elevated toxicities giving rise to no or disadvantageous changes in the therapeutic index of the derivatives. Inclusion of metabolic and toxicological concerns in the drug design process is embodied in the retrometabolic approach. This systematic methodology employs several schemas to provide for the safe targeting of drugs to defined sites or tissues in the body. The retrometabolic approach can be subdivided into soft drug technologies, which provide for agents that are readily and safely deactivated subsequent to exerting their biological effects, and the chemical delivery systems which through multiple enzymatic conversions provide for site-selective delivery. Examples of these chemical techniques to improved drug design are given including a soft steroid for treating ocular inflammation and a brain-targeting chemical delivery system for peptides.