Improving the decision-making process in structural modification of drug candidates: reducing toxicity.
The rule of three, relating to activity-exposure-toxicity, presents the single most difficult challenge in the design and advancement of drug candidates to the development stage. Absorption, distribution, metabolism and excretion (ADME) studies are widely used in drug discovery to optimize this balance of properties necessary to convert lead compounds into drugs that are both safe and effective for human patients. Idiosyncratic drug reactions (IDRs; referred to as type B reactions, which are mainly caused by reactive metabolites) are one type of adverse drug reaction that is important to human health and safety. This review highlights the strategies for the decision-making process involving substructures that, when found in drugs, can form reactive metabolites and are involved in toxicities in humans; the tools used to reduce IDRs are also discussed. Several examples are included to show how toxicity studies have influenced and guided drug design. Investigations of reactive intermediate formation in subcellular fractions with the use of radiolabeled reagents are also discussed.
Nassar
Alaa-Eldin F
AE
Vion Pharmaceuticals Inc., New Haven, CT, USA. nassaral@aol.com
Kamel
Amin M
AM
Clarimont
Caroline
C
D003657:Decision Making; D015195:Drug Design; D004345:Drug Industry / Q000191:economics / Q000379:methods / Q000592:standards; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D021281:Quantitative Structure-Activity Relationship