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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

Topiramate and compounds with similar mechanism of action at the AMPA receptor.
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f10-pmc-2008-021: Topiramate and compounds with similar mechanism of action at the AMPA receptor.

Mentions: The following structures are not very similar chemically but bind to a common target protein, the AMPA receptor. Topiramate is a tetrahydropyrane with one sulphonamide attached. Two acetal groups with two methyl groups each are attached to the molecule to protect the substituents (Fig. 10). Talampanel is a diazepine derivative, the 3-acetylated, 3-4-dihydro analogue of GYKI 52466, which is the prototype of the 2,3-benzodiazepine class of AMPA receptor antagonists (Donevan and Rogawski, 1993). NS1209 is an indole derivative included in a big heterocyclic structure with several attached groups, including one sulphonamide group (Fig. 10). They are large heterogenous molecules and differ in functional groups, which indicate that the whole molecule is not involved in the binding for pharmacological effect.


Modifications of antiepileptic drugs for improved tolerability and efficacy.

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

Topiramate and compounds with similar mechanism of action at the AMPA receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f10-pmc-2008-021: Topiramate and compounds with similar mechanism of action at the AMPA receptor.
Mentions: The following structures are not very similar chemically but bind to a common target protein, the AMPA receptor. Topiramate is a tetrahydropyrane with one sulphonamide attached. Two acetal groups with two methyl groups each are attached to the molecule to protect the substituents (Fig. 10). Talampanel is a diazepine derivative, the 3-acetylated, 3-4-dihydro analogue of GYKI 52466, which is the prototype of the 2,3-benzodiazepine class of AMPA receptor antagonists (Donevan and Rogawski, 1993). NS1209 is an indole derivative included in a big heterocyclic structure with several attached groups, including one sulphonamide group (Fig. 10). They are large heterogenous molecules and differ in functional groups, which indicate that the whole molecule is not involved in the binding for pharmacological effect.

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