Drug Design with ADME in Mind: Recent Paradigm Shifts in Drug Discovery
Borchardt Ronald T. · IOS Press eBooks · 2008
In an attempt to reduce the attrition rate of new chemical entities (NCEs) in development, many pharmaceutical companies have implemented a new drug discovery paradigm that involves optimizing the “pharmacological activity” as well as the “drug-like” properties (e.g. solubility, chemical/enzymatic stability, protein binding, cell permeability) during the lead optimization process in drug discovery. Traditionally, optimizing these “drug-like” properties was not considered by discovery scientists to be their responsibility. Instead, discovery scientists felt that undesirable “drug-like” properties of drug candidates would be “fixed” by preclinical development scientists. However, today most discovery scientists recognize that the “drug-like” properties of NCEs are intrinsic properties of the molecules and that it is their responsibility to optimize both the “pharmacological activity” and the “drug-like” properties of these molecules. In this chapter, the rational for this paradigm shift in drug discovery is discussed. In addition, a case history focusing on the optimization of the “drug-like” properties of cyclic prodrugs of an opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) is provided.