Structural features associated with reactive metabolite formation in clozapine analogues

Uetrecht, Jack; Zahid, Nasir; Tehim, Ashik; Fu, Jianjie; Rakhit, Suman

doi:10.1016/s0009-2797(97)00017-3

Cited by 61 publications

(39 citation statements)

References 6 publications

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“…5d) and JL13, two oxygen isosteres, and also the thiazepine analogue clothiapine is slightly affected in oxidative conditions. This fact is in agreement with our previous data obtained in different experimental procedures for testing oxidative potential [4,5] and reports by other teams [6,29]. The oxidative effect of HRP/H 2 O 2 mixture on binding interaction can be prevented by addition of ascorbic acid to the incubation medium.…”

Section: Resultssupporting

confidence: 93%

“…1) are very sensitive to oxidation while oxygen or sulphur isosteres such as loxapine, clothiapine and JL13 (Fig. 1), possess a very low sensitivity to oxidation [4][5][6]. Despite an extensive effort to examine the impact of such oxidized compounds in different models supposed to be predictive of haematological toxicity to our knowledge no evaluation of such entities in terms of receptor interaction was reported.…”

Section: Introductionmentioning

confidence: 99%

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Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

Dilly

Liégeois

2010

J Comput Aided Mol Des

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The interaction of diazepine analogues like clozapine or olanzapine with D2 receptor was greatly affected by a mixture of HRP/H(2)O(2) known to induce the formation of nitrenium ion. Unlike diazepine derivatives, the oxidative mixture had low impact on the affinity of oxa- and thiazepine derivatives such as loxapine, clothiapine or JL13 for the D2 receptor. Molecular docking simulations revealed a huge difference between the mode of interaction of clozapine nitrenium ion and the parent drug. Electronic and geometric changes of the tricyclic ring system caused by the oxidation appeared to prevent the compound finding the correct binding mode and could therefore explain the difference observed in binding affinities.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

Dilly

Liégeois

2010

J Comput Aided Mol Des

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“…Apparently, diazepine or diarylamine structures are more reactive towards such biochemical systems while analogs with an oxazepine or thiazepine ring seem less sensitive to free radical formation. In another study using hypochlorous acid as an oxidation agent, similar results on various tricyclic analogues were reported (89).…”

Section: Potential Hematotoxicitysupporting

confidence: 55%

JL 13, An Atypical Antipsychotic: A Preclinical Review

Ellenbroek

Liégeois

2003

CNS Drug Reviews

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The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D 2 antagonist, both in vitro and in vivo, with a strong affinity for the D 4 and the 5-HT 2A receptors. It has no affinity for the 5-HT 2C receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum.Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine-and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine.Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug.

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“…Proteins covalently modified with clozapine have been observed in neutrophils of patients being treated with clozapine, which reaffirms the relevance of the in vitro studies [64]. In the case of quetiapine, the bridging nitrogen is replaced with a sulfur atom; consequently, this drug is not bioactivated to the reactive iminium species [65]. Despite administration at doses comparable to clozapine, cases of agranulocytosis with quetiapine are extremely rare.…”

Section: Structure-toxicity Relationshipsmentioning

confidence: 52%

Role of Metabolism in Toxicity of Drugs in Humans

Kalgutkar

Bauman

2012

Encyclopedia of Drug Metabolism and Interactions

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Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites as opposed to the parent molecules from which they are derived are thought to be responsible for the pathogenesis of some IADRs, procedures (reactive metabolite trapping and/or covalent binding) are being incorporated into the discovery screening funnel early on to assess the risk of reactive metabolite formation. Utility of the methodology in structure–toxicity relationships and scope in abrogating the formation reactive metabolites at the lead optimization stage are discussed in this chapter. Interpretation of the output from reactive metabolite assessment assays, however, is confounded by the fact that many successfully marketed drugs are false positives. Therefore, caution must be exercised in deprioritizing a compound based on a positive result, so that the development of a useful and potentially profitable compound will not be unnecessarily halted. Risk mitigation strategies (e.g. competing detoxication pathways, low daily dose, etc.) when selecting reactive metabolite positive for clinical development are also discussed.

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Structural features associated with reactive metabolite formation in clozapine analogues

Cited by 61 publications

References 6 publications

Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

JL 13, An Atypical Antipsychotic: A Preclinical Review

Role of Metabolism in Toxicity of Drugs in Humans

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