LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling

Kadi, Adnan A.; Amer, Sawsan M.; Darwish, Hany W.; Attwa, Mohamed W.

doi:10.1039/c7ra06341e

Cited by 32 publications

(32 citation statements)

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“…Surprisingly, GSH adduct formation was not reported for foretinib 20 , a TKI containing a p ‐fluorinated aniline. On the basis of LC‐MS analyses, Kadi et al observed a reductive defluorination (loss of fluorine) rather than an oxidative defluorination leading to an aminophenol (Figure ).…”

Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

confidence: 99%

“…Foretinib 20 metabolism was investigated in RLM using KCN and methoxylamine since hard electrophile generation can be expected upon bioactivation of morpholine‐containing drugs such as foretinib . Methoxylamine adducts 86 were identified, likely arising from the formation of an aliphatic aldehyde 85 through morpholine ring N ‐dealkylation.…”

Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

confidence: 99%

“…40 Surprisingly, GSH adduct formation was not reported for foretinib 20, a TKI containing a p-fluorinated aniline. On the basis of LC-MS analyses, Kadi et al 46…”

Section: Famitinib Foretinib Gefitinib and Sunitinibmentioning

confidence: 99%

“…Foretinib 20 metabolism was investigated in RLM using KCN and methoxylamine since hard electrophile generation can be expected upon bioactivation of morpholine-containing drugs such as foretinib. 46 Methoxylamine adducts 86 were identified, likely arising from the formation of an aliphatic aldehyde 85 through morpholine ring N-dealkylation. The formation of iminium intermediates 88, evidenced by cyanide adducts 89, was also reported for foretinib 20 after hydroxylation (87) and dehydration of the morpholine ring via a pathway previously described for drugs containing other cyclic tertiary amines 18,44 (Figure 21).…”

Section: Foretinibmentioning

confidence: 99%

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Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Paludetto

Puisset

Chatelut

et al. 2019

Medicinal Research Reviews

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Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life‐threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug‐induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time‐dependent inhibition of the enzyme—also called mechanism‐based inhibition (MBI) or inactivation—can occur and lead to pharmacokinetic drug‐drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM‐positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.

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Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

confidence: 99%

Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

confidence: 99%

“…40 Surprisingly, GSH adduct formation was not reported for foretinib 20, a TKI containing a p-fluorinated aniline. On the basis of LC-MS analyses, Kadi et al 46…”

Section: Famitinib Foretinib Gefitinib and Sunitinibmentioning

confidence: 99%

Section: Foretinibmentioning

confidence: 99%

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Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Paludetto

Puisset

Chatelut

et al. 2019

Medicinal Research Reviews

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“…1) that undergo bioactivation forming iminium ion intermediates [24][25][26] that are hard electrophiles and can be trapped efficiently by KCN. 14,24,25,27 The formed adducts can be separated, detected and characterized using LC-MS/ MS. 21,22,24,28,29 In our work, we are proling unreported in vitro phase I metabolites of brigatinib and we are trying to give insight about the reasons which may be responsible for the observed side effects of BGB. The toxicity prole of BGB includes nausea, fatigue, diarrhea, elevated lipase, dyspnoea, hypertension, hypoxia, pneumonia, elevated amylase, fatigue, pulmonary embolism, elevated ALT, hyponatraemia and hypophosphatemia.…”

Section: Introductionmentioning

confidence: 99%

LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

2018

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Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold

Wurm

Bartz

Schulig

et al. 2022

Archiv der Pharmazie

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K V 7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued K V 7 channel openers flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent K V 7.2/3 opening activity, as evidenced by EC 50 values approaching the single-digit nanomolar range. On the other hand, weighted K V 7.2/3 opening activity data including inactive compounds allowed for the establishment of structure-activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.channels are homo-or heterotetrameric, voltage-gated potassium channels expressed in various tissues, [1] whereby especially heterotetrameric neuronal K V 7 channels predominantly composed of K V 7.2 and K V 7.3 subunits are validated pharmacological targets. [2] In general, K V 7 activation induces hyperpolarization of cell membranes, through which the ion channels contribute to controlling neuronal excitability. By increasing the action potential threshold [3] and medium afterhyperpolarization while reducing spike frequency, [4] K V 7 channels act as a "brake" for hyperexcitability. [5] Moreover, their opening probability can be influenced by small-molecule ligands, [6] making them attractive therapeutic targets, particularly for a range of neurological diseases. [5] For example, the administration of K V 7 channel openers was recently discussed for the therapy of various forms of brain damage, including chronic stress-induced brain injury (CSBI) as well as traumatic brain injury (TBI), for which currently no pharmacotherapeutic treatment options exist. In both cases, animal models suggest that reducing the underlying neuronal hyperexcitability by enhancing K V 7-mediated potassium currents might offer a protective effect. Thus, K V 7 channel activation may be a novel therapeutic intervention

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LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling

Abstract: Using LC-MS/MS, six phase I foretinib metabolites in addition to four potential reactive metabolites, two aldehydes and two iminium ions, were detected and the bioactivation pathways were proposed.

Cited by 32 publications

References 25 publications

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold

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LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling

Abstract: Using LC-MS/MS, six phase I foretinib metabolites in addition to four potential reactive metabolites, two aldehydes and two iminium ions, were detected and the bioactivation pathways were proposed.

Cited by 32 publications

References 25 publications

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic KV7 channel openers: Exploration of a nicotinamide scaffold

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Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold