Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid

Radatz, Matthias; Ehlers, Katharine; Yagen, Boris; Bialer, Meir; Nau, Heinz

doi:10.1016/s0920-1211(97)00095-8

Cited by 59 publications

(79 citation statements)

References 33 publications

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“…Valpromide was a kind gift from Katwijck Chemie (Katwijck, The Netherlands). The VPA structural derivatives used in this study were synthesized according to methods published elsewhere (Nau, 1985;Levi et al, 1997;Radatz et al, 1998;Gravemann, 2002) or as described below (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, valpromide, the slightly teratogenic amide derivative of VPA, had been shown to be metabolized to VPA in vivo (Radatz et al, 1998), whereas valproic hydroxamic acid was shown not to be hydrolyzed (Levi et al, 1997). This raised the question whether a hydrolysis might be the reason for the teratogenic effects of VPA hydroxamates.…”

Section: (1r2s5r)-(؊)-menthylchloroformate and Carboxylic Acid Derimentioning

confidence: 99%

“…The exencephaly rate was determined, as described above, as the model parameter for teratogenicity. These values were considered with previously published exencephaly rates for all other VPA derivatives used in this study (Bojic et al, 1998;Radatz et al, 1998;Volland, 2002) to establish an arbitrary range of teratogenic potency, which is shown in Table 2. The decision criteria range from 0 (no detectable teratogenic potency) to ϩϩϩϩϩ (very high teratogenic potency).…”

Section: Measurement Of Pharmacokinetic Drug Profiles In Micementioning

confidence: 99%

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S-2-PENTYL-4-PENTYNOIC HYDROXAMIC ACID AND ITS METABOLITE S-2-PENTYL-4-PENTYNOIC ACID IN THE NMRI-EXENCEPHALY-MOUSE MODEL: PHARMACOKINETIC PROFILES, TERATOGENIC EFFECTS, AND HISTONE DEACETYLASE INHIBITION ABILITIES OF FURTHER VALPROIC ACID HYDROXAMATES AND AMIDES

Eikel

Hoffmann²,

Zoll³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Structure-activity relationship studies of valproic acid (VPA) derivatives have revealed a quantitative correlation between histone deacetylase (HDAC) inhibition and induction of neural tube defects (NTDs) in the NMRI-exencephaly-mouse model, but this correlation has been, so far, limited to congeners with a carboxylic acid function. Whereas the classical HDAC inhibitor trichostatin A is active only as a hydroxamate but not as a carboxylic acid, we found that neither VPA amides nor hydroxamates inhibit HDACs, but can cause NTDs; e.g., 2-pentyl-4-pentynoic hydroxamic acid with its S-enantiomer being the potent teratogen. We therefore investigated the hypothesis that hydroxamic acid derivatives of VPA might be metabolized in vivo and may possibly be pro-teratogenic, as had been shown for valpromide but not valproic hydroxamic acid. We developed two stereoselective quantification methods based on chiral derivatization of VPA hydroxamates with (1R,2S,5R)-(؊)-menthylchloroformate and carboxylic acid derivatives with (S)-(؊)-1-naphthylethylamine, followed by gas chromatography-nitrogen phosphor detector analysis of biological samples. We then determined the pharmacokinetic profiles of S-2-pentyl-4-pentynoic hydroxamic acid and of S-2-pentyl-4-pentynoic acid in mice. S-2-Pentyl-4-pentynoic hydroxamic acid was found to be extensively metabolized to the corresponding carboxylic acid without affecting the stereochemistry at position C2. Furthermore, the metabolite S-2-pentyl-4-pentynoic acid was found to be very stable in vivo, with an extended half-life of 4.2 h compared with that of VPA, 1.4 h. Comparison of the individual HDAC inhibition abilities of additional VPA amides and hydroxamates, as measured by cellular and enzymatic assays, led us to the conclusion that both classes of VPA derivatives can be pro-teratogenic.Valproic acid (VPA) has been shown to be an inhibitor of histone deacetylases (HDACs), enzymes with a fundamental impact on chromatin remodeling and gene expression of cells (Göttlicher et al., 2001;Phiel et al., 2001). HDACs have chiefly been of interest as possible molecular targets for the treatment of cancer diseases (Yoshida et al., 2001). However, in light of reports that further structural derivatives of VPA were HDAC inhibitors only if they were also teratogenic (Gurvich et al., 2004;Eyal et al., 2005), it has been suggested that VPA might also induce embryonic malformations by its inhibition of HDAC (Gurvich et al., 2005;Eikel et al., 2006), and this possibility has led to new interest in HDACs as molecular targets in toxicology. Recently, we used the NMRI-exencephaly-mouse model (Nau et al., 1981) to demonstrate a quantitative correlation between embryonic malformation and the HDAC inhibition potential of a set of 20 structurally diverse VPA derivatives (Eikel et al., 2006). We showed that the structural prerequisites allowing VPA derivatives to inhibit HDACs are unique and have previously not been shown for other classical HDAC inhibitors such as trichostatin A (TSA) or suberoylanilinh...

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Section: Methodsmentioning

confidence: 99%

Section: (1r2s5r)-(؊)-menthylchloroformate and Carboxylic Acid Derimentioning

confidence: 99%

Section: Measurement Of Pharmacokinetic Drug Profiles In Micementioning

confidence: 99%

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S-2-PENTYL-4-PENTYNOIC HYDROXAMIC ACID AND ITS METABOLITE S-2-PENTYL-4-PENTYNOIC ACID IN THE NMRI-EXENCEPHALY-MOUSE MODEL: PHARMACOKINETIC PROFILES, TERATOGENIC EFFECTS, AND HISTONE DEACETYLASE INHIBITION ABILITIES OF FURTHER VALPROIC ACID HYDROXAMATES AND AMIDES

Eikel

Hoffmann²,

Zoll³

et al. 2006

Drug Metab Dispos

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“…Animal studies reveal a striking difference from valproate in terms of teratogenicity. Thus, in pregnant NMRI mice where valproate produces more than 50% embryotoxicity, valnoctic acid and valnoctamide induce embryotoxicity at frequencies no greater than control (Radatz et al, 1998). One disadvantage of valnoctamide is that it is a potent inhibitor of microsomal epoxide hydrolase so that concomitant administration with carbamazepine causes five-fold increases in the levels of carbamazepine epoxide and clinical signs of toxicity (Pisani et al, 1992;1993).…”

Section: Valproate-like Agentsmentioning

confidence: 99%

Diverse mechanisms of antiepileptic drugs in the development pipeline

2006

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There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cellbased studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABA A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

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“…Some studies suggest that valpromide (similar to VPA, but the carboxyl group is modified to an amide) also has antimanic properties [206]. Valpromide does not inhibit HDAC, does not result in neural tube defects in mouse embryos or the loss of anterior structures that characterizes Xenopus embryos following VPA injection, but does protect against chemically induced seizures in mice [140,[220][221][222][223][224]. Furthermore while the two stereoisomers of VPA have identical antiepileptic properties, only one stereoisomer is teratogenic [224].…”

Section: Valproic Acidmentioning

confidence: 99%

Mood stabilizer psychopharmacology

Gould

Chen

Manji

2002

Clinical Neuroscience Research

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Mood stabilizers represent a class of drugs that are efficacious in the treatment of bipolar disorder. The most established medications in this class are lithium, valproic acid, and carbamazepine. In addition to their therapeutic effects for treatment of acute manic episodes, these medications often are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. While important extracellular effects have not been excluded, most available evidence suggests that the therapeutically relevant targets of this class of medications are in the interior of cells. Herein we give a prospective of a rapidly evolving field, discussing common effects of mood stabilizers as well as effects that are unique to individual medications. Mood stabilizers have been shown to modulate the activity of enzymes, ion channels, arachidonic acid turnover, G protein coupled receptors and intracellular pathways involved in synaptic plasticity and neuroprotection. Understanding the therapeutic targets of mood stabilizers will undoubtedly lead to a better understanding of the pathophysiology of bipolar disorder and to the development of improved therapeutics for the treatment of this disease. Furthermore, the involvement of mood stabilizers in pathways operative in neuroprotection suggests that they may have utility in the treatment of classical neurodegenerative disorders.

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Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid

Cited by 59 publications

References 33 publications

S-2-PENTYL-4-PENTYNOIC HYDROXAMIC ACID AND ITS METABOLITE S-2-PENTYL-4-PENTYNOIC ACID IN THE NMRI-EXENCEPHALY-MOUSE MODEL: PHARMACOKINETIC PROFILES, TERATOGENIC EFFECTS, AND HISTONE DEACETYLASE INHIBITION ABILITIES OF FURTHER VALPROIC ACID HYDROXAMATES AND AMIDES

S-2-PENTYL-4-PENTYNOIC HYDROXAMIC ACID AND ITS METABOLITE S-2-PENTYL-4-PENTYNOIC ACID IN THE NMRI-EXENCEPHALY-MOUSE MODEL: PHARMACOKINETIC PROFILES, TERATOGENIC EFFECTS, AND HISTONE DEACETYLASE INHIBITION ABILITIES OF FURTHER VALPROIC ACID HYDROXAMATES AND AMIDES

Diverse mechanisms of antiepileptic drugs in the development pipeline

Mood stabilizer psychopharmacology

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