Enantioselective synthesis and teratogenicity of propylisopropyl acetamide, a CNS-active chiral amide analogue of valproic acid

Spiegelstein, Ofer; Bialer, Meir; Radatz, Matthias; Nau, Heinz; Yagen, Boris

doi:10.1002/(sici)1520-636x(1999)11:8<645::aid-chir6>3.0.co;2-7

Cited by 21 publications

(11 citation statements)

References 26 publications

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“…The inositol reversal of MTMCD reported here is also consistent with the strong inhibition of inositol synthase activity reported by Shaltiel et al (2004). Finally, we show that PIA Spiegelstein et al (1999). e Data from Loscher and Nau (1985).…”

Section: Discussionsupporting

confidence: 91%

The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

Shimshoni

Dalton²,

Jenkins³

et al. 2006

Mol Pharmacol

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Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of inositol synthase reduces the cellular concentration of myo-inositol, an effect common to the mood stabilizers lithium and carbamazepine. VPA inhibition of histone deacetylases activates Wnt signaling via elevated ␤-catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogs that modulate specific protein targets but leave the others unaffected. Indeed, it has been shown that some nonteratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogs and derivatives that separate anticonvulsant activity from effects on neuronal growth cone morphology. Lithium, carbamazepine, and VPA induce inositol-dependent spread of neuronal growth cones, providing a cell-based assay that correlates with mood-stabilizing activity. We find that two constitutional isomers of VPA, propylisopropylacetic acid and diisopropylacetic acid, but not their corresponding amides, and N-methyl-2,2,3,3-tetramethyl-cyclopropanecarboaxamide are more effective than VPA in increasing growth cone spreading. We show that these effects are associated with inositol depletion, and not changes in ␤-catenin-mediated Wnt signaling. These results suggest a route to a new generation of central nervous system-active VPA analogs that specifically target bipolar disorder.

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Section: Discussionsupporting

confidence: 91%

The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

Shimshoni

Dalton²,

Jenkins³

et al. 2006

Mol Pharmacol

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“…2). [6][7][8]22,[30][31][32][33] The VCD, PID, and DID are more potent as anticonvulsants than their corresponding acids, and act in mice, rats, or dogs as drugs on their own and not as prodrugs to their corresponding acids. 26,27 PID and VCD are CNS-active nonteratogenic chiral constitutional isomers of VPD that are more potent than VPA and have shown stereoselective pharmacokinetics and pharmacodynamics (anticonvulsant activity).…”

Section: Alkyl Analogues Of Vpa and Their Amide Derivativesmentioning

confidence: 99%

“…26,27 PID and VCD are CNS-active nonteratogenic chiral constitutional isomers of VPD that are more potent than VPA and have shown stereoselective pharmacokinetics and pharmacodynamics (anticonvulsant activity). 22,[30][31][32] The (R)-PID was more potent as an anticonvulsant than (S)-PID and (2S,3S)-VCD was more potent than (2R,3S)-VCD. 22,31 PID and VCD (racemate and individual stereoisomers) were also very active in two animal models of difficult-to-treat seizures, namely the hippocampal kindled rat model and the 6 Hz psychomotor seizure model in mice, thus suggesting that these amides could be useful in therapy-resistant epileptic patients.…”

Section: Alkyl Analogues Of Vpa and Their Amide Derivativesmentioning

confidence: 99%

“…22,[30][31][32] The (R)-PID was more potent as an anticonvulsant than (S)-PID and (2S,3S)-VCD was more potent than (2R,3S)-VCD. 22,31 PID and VCD (racemate and individual stereoisomers) were also very active in two animal models of difficult-to-treat seizures, namely the hippocampal kindled rat model and the 6 Hz psychomotor seizure model in mice, thus suggesting that these amides could be useful in therapy-resistant epileptic patients. 22 gabapentin in the rat spinal nerve ligation model for neuropathic pain.…”

Section: Alkyl Analogues Of Vpa and Their Amide Derivativesmentioning

confidence: 99%

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Valproic Acid: Second Generation

2007

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Summary:The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become secondgeneration VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

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“…Enantioselective pharmacokinetics can lead to enantioselective pharmacodynamics in terms of efficacy, toxicity, and clinical outcome. In previous studies, a pharmacokinetic interaction was found between the PID enantiomers in dogs and the pharmacokinetics of PID enantiomers was found to be enantioselective following administration of individual enantiomers (Spiegelstein et al ., 1999a). In this study, the possible pharmacokinetic and/or pharmacodynamic enantiomer–enantiomer interaction of the PID enantiomers was investigated in established rodent models employed in the search for novel anticonvulsant compounds.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents

Isoherranen

Yagen

Woodhead

et al. 2003

British J Pharmacology

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1 Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on dierent methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer ± enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2 Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. . Racemic PID also signi®cantly increased the seizure threshold in this model. 5 Mechanistic studies showed that PID did not aect voltage-sensitive sodium channels or kainate-, GABA-or NMDA-evoked currents. 6 The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer ± enantiomer interaction. 7 This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic pro®le. The enhanced ecacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer ± enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.

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Enantioselective synthesis and teratogenicity of propylisopropyl acetamide, a CNS-active chiral amide analogue of valproic acid

Cited by 21 publications

References 26 publications

The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

Valproic Acid: Second Generation

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents

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