Designing around Structural Alerts in Drug Discovery

Abstract

Cumulative research over several decades has implicated the involvement of reactive metabolites in many idiosyncratic adverse drug reactions (IADRs). Consequently, "avoidance" strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds.Several noteworthy examples where reactive metabolite-related liabilities have been resolved through structure−metabolism studies are presented herein. Considerable progress has also been made in addressing the limitations of the avoidance strategy and further refining the process of managing reactive metabolite issues in drug development. These efforts primarily stemmed from the observation that numerous drugs, which contain structural alerts and/or form reactive metabolites, are devoid of ADRs. The Perspective also dwells into an analysis of the structural alert/ reactive metabolite concept with a discussion of risk mitigation tactics to support the progression of reactive metabolite-positive drug candidates.

Identification of the stable and reactive metabolites of tetrahydropiperine using ultrahigh‐performance liquid chromatography combined with diode‐array detection and high‐resolution mass spectrometry

“…The product ion at m / z 205.0859 was similar to that of the parent compound. The proposed mechanism of the formation of this metabolite involved initial oxidation of the piperidine via bioactivation to a carbinolamine intermediate followed by ring opening to a reactive aldehyde intermediate 18 . To confirm the presence of the aldehyde intermediate, an additional incubation with RLM was performed using methoxylamine as a trapping agent.…”

“…Its MS/MS spectrum (Figure S4, supporting information) displayed two indicative product ions at m / z 508.2102 and 454.1994, which were formed by the losses of glycinyl (75 Da) and glutamyl (129 Da), respectively. The proposed mechanism of the formation of this metabolite (Figure 4) involved initial oxidation of M12 (catechol derivative) to an ortho ‐quinone intermediate, followed by conjugation with the thiol group of GSH 18 …”

Essential Medicinal Chemistry of Essential Medicines

“…Structural alerts (also known as toxicophorics) are functional groups or substructures that are associated with idiosyncratic adverse drug reactions (IADRs) that usually affect liver, skin, and/or blood. 32 The toxicity is unrelated to the pharmacological action of the drug but is usually related to its metabolism into electrophilic reactive metabolites that covalently modify host proteins. 33 Starting from the seminal list reported by Nelson, the number of structural alerts has been implemented over the years, reaching hundreds of toxicophores, with the aim of minimizing the attrition related to the toxicity of drug candidates.…”

Algorithm for Extraction of Sub-Structure from Co-Crystallized PDB Ligand for Selective Targeting

“…Molecular fragments with high chemical reactivity were also considered as structural alerts and were avoided to reduce toxicity in pharmaceuticals (Limban et al, 2018). Structure-metabolism studies are known to resolve reactive metabolite-related liabilities by "avoidance" strategies for exclusion of structural alerts and possible termination of reactive metabolite-positive compounds (Kalgutkar, 2019). In a study, to define the structural alerts for generation of reactive metabolites from drugs, systematic approach was used by involving macromolecules leading to immune responses (Claesson and Minidis, 2018) (Kalgutkar, 2019).…”

“…Structure-metabolism studies are known to resolve reactive metabolite-related liabilities by "avoidance" strategies for exclusion of structural alerts and possible termination of reactive metabolite-positive compounds (Kalgutkar, 2019). In a study, to define the structural alerts for generation of reactive metabolites from drugs, systematic approach was used by involving macromolecules leading to immune responses (Claesson and Minidis, 2018) (Kalgutkar, 2019). In another study, to analyze the drug effect, classifier based approach was adopted for identification of association between drug substructures and protein domain.…”