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Modifications of antiepileptic drugs for improved tolerability and efficacy.

Landmark CJ, Johannessen SI - Perspect Medicin Chem (2008)

Bottom Line: The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds.Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity.These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

View Article: PubMed Central - PubMed

Affiliation: Cecilie Johannessen Landmark, Associate Professor, Dept. of Pharmacy, Faculty of Health Sciences, Oslo University College, Pilestredet 50, N-0167 Oslo, Norway.

ABSTRACT

Introduction: A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties.

Material and method: AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches.

Results and discussion: Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABA(A) receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone).

Conclusion: Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

No MeSH data available.


Related in: MedlinePlus

Lamotrigine and its derivative JZP-4.
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f6-pmc-2008-021: Lamotrigine and its derivative JZP-4.

Mentions: Lamotrigine is a 1,2,4-triazine, with two chloride atoms attached (Fig. 6). In JZP-4, one nitrogen atom has been removed from the cyclic structure, and another chloride is attached to the aromatic ring (Fig. 6). The two drugs are different in structure since cyclic structures with two nitrogen atoms are commonly occurring in biological molecules, while three nitrogens are not common. Both molecules are neutral in physiological pH. The modifications in JZP-4 may affect the metabolic route of elimination for lamotrigine.


Modifications of antiepileptic drugs for improved tolerability and efficacy.

Landmark CJ, Johannessen SI - Perspect Medicin Chem (2008)

Lamotrigine and its derivative JZP-4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2746576&req=5

f6-pmc-2008-021: Lamotrigine and its derivative JZP-4.
Mentions: Lamotrigine is a 1,2,4-triazine, with two chloride atoms attached (Fig. 6). In JZP-4, one nitrogen atom has been removed from the cyclic structure, and another chloride is attached to the aromatic ring (Fig. 6). The two drugs are different in structure since cyclic structures with two nitrogen atoms are commonly occurring in biological molecules, while three nitrogens are not common. Both molecules are neutral in physiological pH. The modifications in JZP-4 may affect the metabolic route of elimination for lamotrigine.

Bottom Line: The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds.Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity.These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

View Article: PubMed Central - PubMed

Affiliation: Cecilie Johannessen Landmark, Associate Professor, Dept. of Pharmacy, Faculty of Health Sciences, Oslo University College, Pilestredet 50, N-0167 Oslo, Norway.

ABSTRACT

Introduction: A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties.

Material and method: AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches.

Results and discussion: Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABA(A) receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone).

Conclusion: Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

No MeSH data available.


Related in: MedlinePlus