Identification of a pyridinium metabolite in human urine following a single oral dose of 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid monohydrochloride (CI-966), a .gamma.-aminobutyric acid uptake inhibitor

Radulovic, Louis L.; Woolf, Thomas F.; Bjorge, S. M.; Taylor, Charles W.; Reily, Michael D.; Bockbrader, Howard N.; Chang, Tsun

doi:10.1021/tx00033a014

Cited by 9 publications

(7 citation statements)

References 17 publications

(19 reference statements)

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“…This finding is consistent with O-methylation of paroxetine catechol by catechol- O -methyltransferase to the corresponding guaiacol regioisomers, which are the major metabolites of paroxetine in humans . Certain cyclic amine moieties such as the N -substituted-4-aryl-1,2,3,6-tetrahydropyridine and 4-aryl- N -substitutedpiperidin-4-ol, however, will (and should) deserve special scrutiny with respect to their metabolism by MAO and P450 to cyclic dihydropyridinium and the stable pyridinium metabolites, which have been linked with neurodegenerative effects including parkinsonism and tardive dyskinesia in humans as illustrated with the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and the neuroleptic agent haloperidol and related analogues. ,,− …”

Section: Perspectivesupporting

confidence: 74%

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Kalgutkar

2016

Chem. Res. Toxicol.

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Soft electrophiles (e.g., epoxides, quinones, quinone-imines, quinone-methides, etc.) generated via the oxidative bioactivation of phenyl, phenolic, amino-, and alkylphenolic substituents can be trapped with nucleophiles of comparable softness (e.g., glutathione or cysteine) in reactive metabolite screens. In contrast, hard nucleophiles such as cyanide and amines are frequently utilized to trap hard electrophiles (e.g., iminiums and aldehydes) that result from the oxidative bioactivation of cyclic (or acylic) amines and primary alcohols. In some instances, soft sulfydryl nucleophiles have also been utilized to trap aldehydes to yield cyclized thiazolidine adducts. Case studies where hard electrophiles are thought to be responsible for cytochrome P450 inactivation, genotoxicity, and/or target organ toxicity in animals have been presented. The association of hard electrophiles with immune-mediated idiosyncratic adverse drug reactions is less clear given the paucity of available examples and the fact that several marketed drugs containing cyclic amine motifs can generate hard electrophiles via α-carbon ring oxidation. This perspective examines available data associating toxicity with the formation of hard electrophilic intermediates from small molecule drugs/drug candidates. Pragmatic risk mitigation strategies around unwarranted idiosyncratic toxicity risks with drug candidates that generate hard electrophiles are also discussed against the backdrop of marketed agents that possess analogous cyclic amine framework.

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Section: Perspectivesupporting

confidence: 74%

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Kalgutkar

2016

Chem. Res. Toxicol.

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“…exposure. Although details concerning the mechanism of neurotoxicity of 93 and 94 remain unclear, it is noteworthy to point out that the major urinary metabolite of 93 and 94 are the corresponding pyridinium species 95 and 96, respectively[123].…”

mentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

576

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities 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.

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“…We chose to avoid further derivatives of CI-966, given its known toxicity and the poor brain uptake of [ 18 F]3 . 6,9 Therefore, we were attracted by a new series of GAT-1 inhibitors reported by Wanner and colleagues in 2013. 20 These compounds consisted of a nipecotic acid core and an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer, and we selected compound 10 as the lead because of its potency in a functional [ 3 H]GABA uptake assay (pIC 50 = 5.73±0.14 (( E )- 10 ) and 6.47±0.08 (( Z )- 10 )) and >100-fold selectivity for GAT-1 over GAT-2, -3 and -4.…”

Section: Resultsmentioning

confidence: 99%

“…We concluded from these initial studies that N -methylnipecotic acid derivatives were not sufficiently drug-like to penetrate the CNS (Table ), and so turned our attention to developing a radiotracer that was based upon nipecotic acid but with improved drug-like properties. We chose to avoid further derivatives of CI-966, given its known toxicity and the poor brain uptake of [ 18 F]3 . , Therefore, we were attracted by a new series of GAT-1 inhibitors reported by Wanner and colleagues in 2013 . These compounds consisted of a nipecotic acid core and an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer, and we selected compound 10 as the lead because of its potency in a functional [ 3 H]GABA uptake assay (pIC 50 = 5.73 ± 0.14 (( E )- 10 ) and 6.47 ± 0.08 (( Z )- 10 )) and >100-fold selectivity for GAT-1 over GAT-2, −3 and −4 .…”

Section: Resultsmentioning

confidence: 99%

“…6 Although exhibiting low brain permeability, [ 18 F]3 did have a heterogeneous in vivo brain distribution similar to that obtained using [ 3 H]tiagabine in vitro and ex vivo . 7,8 These early studies were encouraging, but the combination of (1) a still rudimentary understanding of the pharmacology and brain distribution of the GABA transporters, (2) a lack of published structure-activity studies for GAT-1 inhibitors, (3) concerns over potential adverse pharmacological effects of this family of GAT-1 inhibitors, 9 and (4) difficult chemistry to obtain the high specific activities needed for human studies led us to cease further effort in development of GABA transporter inhibitor radioligands. Subsequent efforts by others in syntheses of radiolabeled GABA transporter inhibitors (GAT-1 and GAT-3) for imaging have also been unsuccessful.…”

Section: Introductionmentioning

confidence: 99%

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Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1

Sowa

Brooks

Shao

et al. 2018

ACS Chem. Neurosci.

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In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4-[F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z)-[F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.

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Identification of a pyridinium metabolite in human urine following a single oral dose of 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid monohydrochloride (CI-966), a .gamma.-aminobutyric acid uptake inhibitor

Cited by 9 publications

References 17 publications

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1

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