Functionalized DL-amino acid derivatives. Potent new agents for the treatment of epilepsy

Conley, Judith D.; Kohn, Harold

doi:10.1021/jm00386a021

Cited by 55 publications

(43 citation statements)

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“…In 1985, Cortes et al reported that the amino acid derivative N-acetyl-DL-alanine-Nbenzylamide was protective in the mouse MES test with modest potency (ED 50 , 77 mg/kg; Conley et al, 1987). Examination of a large number of derivatives that conform to the general N-benzyl-2-acetamidopropionamide structure (R 1 =CH 3 ; R 3 =phenyl in the model structure of Fig.…”

Section: Functionalized Amino Acidsmentioning

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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Section: Functionalized Amino Acidsmentioning

confidence: 99%

Diverse mechanisms of antiepileptic drugs in the development pipeline

2006

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“…This method is analogous to that reported for 1, where H-Phe-benzylamine was coupled with Boc-D-Leu-OH, followed by acid catalysed Boc cleavage. In detail, compound 3 was synthesised by the reaction of 6 11,12 with acetyl-D-Leu-OH using the HATU coupling reagent in good yield (72%). Compound 4 was synthesised by coupling of 6 with Boc-D-Leu-OH and HATU to obtain compound 7 in good yield (76%), followed by Boc cleavage of 7 to give the dipeptide 8, the free amine equivalent of 1, in moderate yield (65%).…”

Section: Resultsmentioning

confidence: 99%

D-Leu-L-Phe-containing dipeptide inhibitors of α-chymotrypsin – the role of the N- and C-termini in enzyme affinity

Pearson¹,

Abell²

2008

Arkivoc

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“…In the recent years, Kohn and coworkers have reported on the anticonvulsant activity of a series of functionalized amino acids [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] (FAA) 5 ( Fig. 6).…”

Section: Derivatives Of Amino Acidsmentioning

confidence: 99%

New Anticonvulsant Agents

Malawska

2005

CTMC

144

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The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of gamma-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.

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Functionalized DL-amino acid derivatives. Potent new agents for the treatment of epilepsy

Cited by 55 publications

References 0 publications

Diverse mechanisms of antiepileptic drugs in the development pipeline

Diverse mechanisms of antiepileptic drugs in the development pipeline

D-Leu-L-Phe-containing dipeptide inhibitors of α-chymotrypsin – the role of the N- and C-termini in enzyme affinity

New Anticonvulsant Agents

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