Drug−Protein Adducts:  An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and Development

It is generally accepted that there is neither a well-defined nor a consistent link between the formation of drug−protein adducts and organ toxicity. Because the potential does exist, however, for these processes to be causally related, the general strategy at Merck Research Laboratories has been to minimize reactive metabolite formation to the extent possible by appropriate structural modification during the lead optimization stage. This requires a flexible approach to defining bioactivation issues in a variety of metabolism vectors and typically involves the initial use of small molecule trapping agents to define the potential for bioactivation. At some point, however, there is a requirement to synthesize a…