Commentary: Discovery Toxicology—A Nascent Science

Research groups with a gestalt similar to that of DuPont Phamaceuticals’ Discovery Toxicology are arising within an increasing number of pharmaceutical and biotechnology companies and in the chemical industry. This commentary provides a historical perspective on this development and describes the diverse functions performed by 1 such group. The role of this group is illustrated by a series of investigations that affected the development of a novel class of anti-inflammatory drugs. The traditional approach to drug development employed whole-animal pharmacology screens. The objective of such screens was to identify molecules with desired pharmacology, such as the abilities to reduce xenograft tumor growth, lower blood pressure, induce diuresis, etc. These approaches did not require a detailed understanding of biochemical mechanisms of action; this goal was pursued later in the development process. Although whole-animal screens did not afford the highthroughput screening currently employed, molecules identified by this approach necessarily had at least some of the desirable formulation characteristics, pharmacokinetics, pharmacodynamics, and toxicity information to facilitate drug candidate selection. The product of this process was a small number of lead molecules entering the safety evaluation process. In recent years, the molecular definition of desirable therapeutic targets has displaced the whole-animal pharmacology screens with high-throughput, frequently noncell-based assays in New Leads Discovery groups. Large numbers of candidate pharmacophores can be selected and rapid progress made toward optimization of structure-activity relationships (SAR) before compounds are exposed either to cells or to whole animals. Proceeding into preclinical development following pharmacokinetic and pharmacodynamic optimization of such pharmacophores is often fraught with pitfalls related to unexpected manifestations of pharmacology and toxicity. By moving initial toxicology and pharmacology assessments earlier within the drug discovery process, potential drug liabilities may be identified prior to expenditure of considerable chemical and pharmacologic resources. The early identification of compound liabilities relating to pharmacology or toxicity is the essence of Discovery Toxicology. IDENTIFICATION OF POTENTIAL LIABILITIES