Synthesis and anticonvulsant activities of .alpha.-heterocyclic .alpha.-acetamido-N-benzylacetamide derivatives

Kohn, Harold; Kn, Sawhney; Bardel, Patrick; Dw, Robertson; Jd, Leander

doi:10.1021/jm00074a016

Cited by 49 publications

(81 citation statements)

References 16 publications

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“…A similar finding was observed in the model but using the Sprague Dawley Rat. This finding was surprising since earlier results suggested that substituents placed at the 4′-position of the N -benzyl amide moiety in ( R )- 3 resulted in a significant loss of MES seizure protection upon administration to mice 15,26,27. For example, we reported previously that the MES ED 50 values for the 4′-NO 2 (( R )- 48 ) and the 4′-NCS (( R )- 59 ) analogs were 100–300 and 24 mg/kg, respectively 26.…”

Section: Resultsmentioning

confidence: 80%

“…Earlier studies of 2 indicated that substituting a N -benzyl group led to compounds with diminished anticonvulsant profiles 15,26,27. When the 4′-substituted 2 compounds were compared with the 3′-substituted isomers, the 4′-substituted derivatives provided significantly greater seizure protection as defined in the rodent MES seizure model 18,26.…”

Section: Resultsmentioning

confidence: 97%

“…This finding was surprising since preliminary studies with other 2s suggested that substitutions made at this specific site were not very promising candidates. 15,26,27…”

mentioning

confidence: 99%

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Synthesis and Anticonvulsant Activities of (R)-N-(4′-Substituted)benzyl 2-Acetamido-3-methoxypropionamides

et al. 2009

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The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3) has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that non-bulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were either comparable with or exceeded that of (R)-3, and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.Epilepsy, a major neurological disorder that affects all populations, 1 describes the types of recurrent seizures produced by paroxysmal, excessive, synchronous neuronal discharges in the brain. 2,3 In the United States alone, over 2 million people suffer from epilepsy and its sequelae; 340,000 are children. 4 For many of these individuals, the disabilities and associated neuropsychological and behavioral factors adversely affect their quality of life. The lifestyle restrictions plus the large expense for treatment, lost productivity, and rehabilitation result in a huge cost to society. 4 The treatment mainstay for patients with epileptic disorders has been the long-term and consistent administration of anticonvulsant drugs. 5,6 Unfortunately, current medications are ineffective for approximately one-third of these patients. 7 Many continue to have seizures, while others experience disturbing side effects (e.g., drowsiness, dizziness, nausea, liver damage). 8 Thus, there is a need for more efficacious drugs that function by different pharmacological pathways.CORRESPONDING AUTHOR: Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568 and Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290, hkohn@email.unc.edu, Telephone: 919-843-8112, Fax number: 919-966-0204. Supporting Information Available: Synthetic procedures for the intermediates leading to the preparation of (R)-4, 7-31, 33-39, 60, and 61, and (S)-11, 21, 23, 26, 28, 29, 34, and 38, elemental analyses, 1 H and 13 C NMR spectra of compounds evaluated in this study. This material is available free of charge via the internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2011 February 11. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1985, we discovered a novel class of anticonvulsant agents, termed functionalized amino acids (FAA, a 1). ...

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 97%

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Synthesis and Anticonvulsant Activities of (R)-N-(4′-Substituted)benzyl 2-Acetamido-3-methoxypropionamides

et al. 2009

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“…Fourth, syntheses of both enantiomeric forms of the lacosamide AB&CR agents 3 are necessary. A distinguishing feature of 1 is that its anticonvulsant activity resides principally in the D -configuration 11-13,15,18. Accordingly, preferential enantioselective irreversible inactivation with the AB&CR agents serves as an important measure of target site specificity 28,29.…”

Section: Resultsmentioning

confidence: 99%

Lacosamide Isothiocyanate-Based Agents: Novel Agents To Target and Identify Lacosamide Receptors

et al. 2009

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Abstract(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide), has recently gained regulatory approval for the treatment of partial-onset seizures in adults. Whole animal pharmacological studies have documented that (R)-2 function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogs, 3, that contain "affinity bait (AB)" and "chemical reporter (CR)" functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy) propionamide ((R)-9), exhibited excellent seizure protection in mice and, like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2.

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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

145

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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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Synthesis and anticonvulsant activities of .alpha.-heterocyclic .alpha.-acetamido-N-benzylacetamide derivatives

Cited by 49 publications

References 16 publications

Synthesis and Anticonvulsant Activities of (R)-N-(4′-Substituted)benzyl 2-Acetamido-3-methoxypropionamides

Synthesis and Anticonvulsant Activities of (R)-N-(4′-Substituted)benzyl 2-Acetamido-3-methoxypropionamides

Lacosamide Isothiocyanate-Based Agents: Novel Agents To Target and Identify Lacosamide Receptors

New Anticonvulsant Agents

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