There are five categories:
- Broad reviews
- Focus on toxicological and strategy aspects
- Focus on screening techniques
- Papers on in vitro vs. in vivo data
- Special aspects, in particular carboxylic acids
1. Broad reviews
Managing the Liabilities Arising from Structural Alerts: A Safe Philosophy for Medicinal Chemists. PJ Edwards and C Sturino. Curr Med Chem. 2011, 18, 3116-3135. This review on the use of structural alerts sadly has been overlooked by us and others and is therefore placed first for the time being.
Metabolism and Bioactivation: It’s Time to Expect the Unexpected. JP Driscoll et al. J. Med. Chem. 2020, 63, 6303-14.
Designing around Structural Alerts in Drug Discovery. AS Kalgutkar. J Med Chem. 2019, XX, xxxx
Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs. A Claesson & A Minidis. Chem Res Toxicol. 2018, 31, 389-411.
Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury. RJ Weaver et al. Exp. Op. Drug Met & Tox. 2017, 13, 767-782.
Detecting reactive drug metabolites for reducing the potential for drug toxicity. MP Grillo. Expert Opin Drug Metab Tox 2015, 11, 1281-1302.
Predicting Toxicities of Reactive Metabolite–Positive Drug Candidates. Kalgutkar & Dalvie (Pfizer). Ann Rev Pharmacol Tox 2015, 55, 35-54.
Gauging Reactive Metabolites in Drug-Induced Toxicity. RM Eno & MD Cameron. Curr Med Chem, 2015, 22, 465-489.
On Mechanisms of Reactive Metabolite Formation from Drugs . A Claesson & O Spjuth. Mini-Rev Med Chem 2013, 13, 720-729.
In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs. Thompson et al. (AZ). Chem Res Toxicol 2012, 25, 1616–1632
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. AF Stepan et al. (mostly Pfizer). Chem Res Toxicol 2011, 24, 1345–1410.
Bioactivation of Drugs: Risk and Drug Design. JS Walsh & GT Miwa. Ann Rev Pharmacol Toxicol 2011, 51, 145-167
Managing the challenge of chemically reactive metabolites in drug development. KB Park et al. Nature Reviews Drug Discovery 2011, 10, 292–306.
Strategies and Chemical Design Approaches to Reduce the Potential for Formation of Reactive Metabolic Species. Argikar et al. (Novartis USA). Curr Topics Med Chem 2011, 11, 419-449.
Cheminformatics Analysis of Assertions Mined from Literature That Describe Drug-Induced Liver Injury in Different Species. Fourches et al. (UNC Chapel Hill). Chem Res Toxicol 2010, 23, 171–183.
Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective. Tang & Lu. Drug Metabolism Reviews 2010, 42, 225-249.
Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity? Kalgutkar & Didunk (Pfizer). Chemistry & Biodiversity 2009, 6, 2115-2137
Minimizing metabolic activation during pharmaceutical lead optimization: Progress, knowledge gaps and future directions. Kumar et al. (Merck). Current Opinion in Drug Discovery and Development 2008 11:43-52.
Chemical toxicology: reactive intermediates and their role in pharmacology and toxicology. John Erve (Wyeth). Exp. Op. Drug Met & Tox. 2006, 9, 923.
Minimising the potential for metabolic activation in drug discovery. Kalgutkar et al. (Pfizer). Expert Opinion on Drug Metabolism and Toxicology, 2005, 1, 91-142.
A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups. Kalgutkar et al. (Pfizer). Current Drug Metabolism. 2005, 6, 161-225.
Drug−Protein Adducts: An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and Development. Evans et al. (Merck). Chem. Res. Toxicol., 2004, 17 (1), 3–16.
Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Peter Guengerich (Vanderbilt Univ.). Arch. Biochem. Biophys. 2003, 409, 59-71.
Structure toxicity relationships – how useful are they in predicting toxicities of new drugs. Sidney Nelson. Adv. Med. Exp. Biol. 2001, 500, 33-43.
2. Focus on toxicological and strategy aspects
Drug Induced Liver Injury (DILI). Mechanisms and Medicinal Chemistry Avoidance/Mitigation Strategies. BH Norman. J. Med. Chem. 2020,
Safety Assessment of Acyl Glucuronides – A Simplified Paradigm. DA Smith,
Minimizing the risk of chemically reactive metabolite formation of new drug candidates: implications for preclinical drug design. A Brink et al. Drug Discov Today 2017, 22, 751-756
Reactive Metabolites: Current and Emerging Risk and Hazard
Assessments. RA Thompson et al. (AZ). Chem Res Toxicol 2016, 29, 505-33
Managing the challenge of chemically reactive metabolites in drug development. BK Park and 18 other experts. Nature Reviews Drug Discovery 2011,10, 292-306.
Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. RA Thompson et al. (AZ). Chemico-Biol. Interact. 2011, 192, 65-71.
Idiosyncratic Drug Reactions: Past, Present, and Future. Jack Uetrecht (Univ. of Toronto). Chem. Res. Toxicol. 2008, 21, 84-92.
3. Focus on screening techniques
Practical approaches to resolving reactive metabolite liabilities in early discovery. Dalvie et al. (Pfizer). Drug Metab. Rev. 2015, 47, 56-70
In Vitro Screening Techniques for Reactive Metabolites for Minimizing Bioactivation Potential in Drug Discovery. Prakash et al. (Pfizer). Current Drug Metabolism, 2008, 9, 952-964.
4. Papers on in vitro vs. in vivo data
Can In Vitro Metabolism-Dependent Covalent Binding Data in Liver Microsomes Distinguish Hepatotoxic from Nonhepatotoxic Drugs? An Analysis of 18 Drugs with Consideration of Intrinsic Clearance and Daily Dose. Obach et al. (Pfizer). Chem. Res. Toxicol. 2008, 21, 1814–1822
Can In Vitro Metabolism-Dependent Covalent Binding Data in Liver Microsomes Distinguish Hepatotoxic from Nonhepatotoxic Drugs? An Analysis Using Human Hepatocytes and Liver S-9 Fraction. Bauman et al. (Pfizer). Chem. Res. Toxicol., 2009, 22 (2), 332–340
Prediction of in Vivo Potential for Metabolic Activation of Drugs into Chemically Reactive Intermediate: Correlation of in Vitro and in Vivo Generation of Reactive Intermediates and in Vitro Glutathione Conjugate Formation in Rats and Humans. Masubuchi et al.(Daiichi). Chem. Res. Toxicol., 2007, 22, 455-464.
A Zone Classification System for Risk Assessment of Idiosyncratic Drug Toxicity Using Daily Dose and Covalent Binding. S. Nakayama, et al. (Daiichi), Drug Metab. Dispos. 37 (2009) 1970.
Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins. Usui et al. (Dainippon Sumitomo). Drug Metab. Dispos. 37:2383–2392, 2009
5. Special aspects, in particular carboxylic acids
Acyl-CoA thioesters as chemically-reactive intermediates of carboxylic acid-containing drugs. MP Grillo,
C Li, LZ Benet. Med. Chem. Res. 2023, https://doi.org/10.1007/s00044-023-03144-5
A review of the synthesis, bioanalysis, and chemical reactivity of xenobiotic acyl-coenzyme a thioesters. C Skonberg and J Olsen. Med. Chem. Res. 2023, https://doi.org/10.1007/s00044-023-03129-4
Acyl glucuronide reactivity in perspective. PR Bradshaw et al. Drug Disc. Today. 2020, 25, 1639-50
New Perspectives on Drug-Induced Liver Injury Risk Assessment of Acyl Glucuronides. M Walles et al. Chem. Res. Toxicol. 2020, 33, 1533
Safety Assessment of Acyl Glucuronides – A Simplified Paradigm. DA Smith,
Acyl glucuronide metabolites: Implications for drug safety assessment. TR Van Fleet et al. Toxicol. Letters 2017, 272, 1–7
Toxicological potential of acyl glucuronides and its assessment. A Iwamura, M Nakajima, S Oda, T Yokoi. Drug Metab. Pharmacokin. 2016, 32, 2-11
Important article: Significantly Different Covalent Binding of Oxidative Metabolites,
Acyl Glucuronides, and S‑Acyl CoA Conjugates Formed from Xenobiotic Carboxylic Acids in Human Liver Microsomes. M Darnell, L Weidolf et al. (AZ). Chem. Res. Toxicol., 2015, 28, 886–896
Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated. T Lassila et al. Chem. Res. Toxicol., 2015, 28, 2292–2303
A new rapid in vitro assay for the assessment of the reactivity of acyl glucuronides. S Zhong et al. Drug Metab. Disp. 2015,
Dissecting the Reaction of Phase II Metabolites of Ibuprofen and Other
NSAIDS with Human Plasma Protein. R Nygaard Monrad et al. Chem Sci. 2014, 5, 3789-94.
Metabolism of Xenobiotic Carboxylic Acids – Focus on Coenzyme A Conjugation, Reactivity and Interference with Lipid Metabolism. M Darnell & L Weidolf (AZ). Chem. Res. Toxicol. 2013, 26, 1139-1155
Metabolic activation of carboxylic acids. Skonberg et al. (Copenhagen). Exp. Opin. Drug Metab. Tox. 2008, 4, 425-438
Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks. Orr et al. (Pfizer). J Med Chem 2012, 55, 4896-4933.
Acyl glucuronide reactivity in perspective: biological consequences. Bailey & Dickinson. Chem-Biol Interact 2003, 145, 117-137