Prodrugs: Challenges and Rewards--Parts I and II

Abstract

This book is a collaborative effort by the editors and many authors and coauthors to address the need for an update on the challenges and rewards of using prodrugs to effect better drug delivery. In the middle of the last century, Adrian Albert was the first to use the terms "pro-drug" and "pro-agent" in both an early paper and various editions of his book "Selective Toxicity" (see the first chapter for more details). It was clear from these early publications that the terms described bioreversible chemical derivatives of medicinal agents used to effect better activity, delivery, formulation, or targeting to tissues. Albert recognized that while many molecules might be effective at the cellular level, the properties that made them useful were not necessarily those that allowed their formulation, delivery, or targeting. The astute reader will recognize that this concept is as applicable now as it was in the 1950s. At present we use terms such as "drugability" or the need for "druglike" properties to describe the requirement to incorporate these properties so that the complex synthetic molecules of today can be clinically tested and potentially commercialized. In the mid-1980s, with the advent of molecular biology and the availability of pure protein targets, many new chemical entities were found to be effective at the molecular/receptor level but ineffective as molecules of commercial value. Maximizing binding often led to molecules so chemically constrained that drug-like properties could no longer be built in without significantly compromising activity. Some have referred to this as the "high affinity trap." Of necessity, this began to change. The papers and talks given by C.A. Lipinski and his collaborators made medicinal chemists aware that high throughput screening for drug-like properties should be performed in parallel with molecular/receptor screens so that leads and, ultimately, drug candidates had a better chance of clinical success. Therefore, in the two parts of this book, we attempt to present the current status of the prodrug concept and its many applications and to highlight its many successes in overcoming the formulation and delivery of problematic drugs. Dictated by the quantity of material, this book is divided into two parts