Structural Alerts for Toxicity
@article{Blagg2020StructuralAF, title={Structural Alerts for Toxicity}, author={Julian Blagg}, journal={Medicinal Chemistry for Practitioners}, year={2020} }
This chapter summarizes structural alerts where there is a significant weight of evidence that their incorporation into a drug candidate molecule is likely to result in a higher than average incidence of attrition due to adverse safety/or toxicity findings. The mechanism of formation of reactive metabolites from each structural alert is summarized. The structure–toxicity relationships and the boundary of definition for each structural alert are discussed. The benefits of low exposure and…
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References
SHOWING 1-10 OF 177 REFERENCES
Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States.
- BiologyChemical research in toxicology
- 2011
While RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, the analysis suggests a need for a more integrated screening paradigm for chemical hazard identification in drug discovery.
Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?
- Biology, ChemistryChemistry & biodiversity
- 2009
Current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these assays are outlined.
A comprehensive listing of bioactivation pathways of organic functional groups.
- BiologyCurrent drug metabolism
- 2005
This review aims to serve as a resource describing the structural diversity of functional groups or structural motifs commonly utilized in drug design efforts as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.
Minimising the potential for metabolic activation in drug discovery
- BiologyExpert opinion on drug metabolism & toxicology
- 2005
Major themes explored in this review include a comprehensive cataloguing of bioactivation pathways of functional groups commonly utilised in drug design efforts with appropriate strategies towards detection of corresponding reactive intermediates.
Toxicophores, reactive metabolites and drug safety: when is it a cause for concern?
- BiologyExpert review of clinical pharmacology
- 2008
The basic methodology that is currently utilized to evaluate the bioactivation potential of new compounds is reviewed, with particular emphasis on the advantages and limitation of these assays.
Identification of the structural requirements for mutagencitiy, by incorporating molecular flexibility and metabolic activation of chemicals. II. General Ames mutagenicity model.
- Biology, ChemistryChemical research in toxicology
- 2007
The focus of the present work was to build a general Mutagenicity model predicting mutagenicity with respect to any of the Ames tester strains, found to have 82% sensitivity, 89% specificity, and 88% concordance for training set chemicals.
Screening of drug candidates for their drug--drug interaction potential.
- Biology, MedicineCurrent opinion in chemical biology
- 2001
Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development.
- BiologyChemical research in toxicology
- 2004
This paper serves to provide one pragmatic approach to addressing the issue of bioactivation from an industry viewpoint based on protocols adopted by Merck Research Laboratories.
Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions.
- BiologyCurrent drug metabolism
- 2007
A comprehensive analysis of the biochemical basis and known structure-activity relationships for P 450 inactivation by xenobiotics is described and the current state-of-the-art of the methodology used in predicting the magnitude of DDIs using in vitro P450 inactivation data and human pharmacokinetic parameters is discussed in detail.