Antiepileptic activity of 1,3-dihexadecanoylamino-2-valproyl-propan-2-ol, a prodrug of valproic acid endowed with a tropism for the central nervous system

Mergen, F.; Lambert, Didier M.; Saraiva, J. C. Goncalves; Poupaert, Jacques H.; Dumont, Pierre

doi:10.1111/j.2042-7158.1991.tb03491.x

Cited by 18 publications

(3 citation statements)

References 19 publications

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“…With the exception of compound 17, all cyclic compounds showed no sedative effects at the ED50 dose. This property was exploited in compounds 16 and 17, which preserved or even exceeded the potency of 2-ene VPA while remaining free of substantial sedation.…”

Section: Resultsmentioning

confidence: 99%

“…The corresponding carboximides 20a-f and 21a,b were then prepared as described by Evans (±)-3-(l-Oxohexyl)-4-(l-methylethyl)-2-oxazolidinone (20d): 7.49 g (64%, bp 104-6 °C/0.05 mmHg); -NMR (200 MHz, acetone-*) <3: 0.68-0.80 (9H, m, 3 x CH3), 1.09-1.23 (4H, m, CH3CH2CH2), 1. 38 (±)-3-(l-Oxo-3-methylbutyl)-4-(l-methylethyl)-2-oxazolidinone (20e): 6.78 g (91%, bp 94-98 °C/0.05 mmHg) at 6U scale of above; -NMR (200 MHz, acetone-*) <5: 0.80-1.00 (12H, m, CH(CH3)2), 2.00-2.12, 2.12-2.41 (1H, 1H, m, m, 2 x CH(CH3)2), 2.60 (2H, dd, =7 = 7.0, 15. (± )-3-(l-Oxo-2-cyclopentylethyl)-4-(l -methylethyl)-2oxazolidinone (20f): 9.13 g (82%, bp 127-130 °C/0.2 mmHg); mp 33-37 °C; -NMR (300 MHz, acetone-*) ó: 0.88, 0.95 (3H, 3H, d, d, =7 = 7 Hz each, CH(CH3)2), 1.10-1.32 (2H, m, cyclopentyl), 1.46-1.73 (4H, m, cyclopentyl), 1.73-1.92 (2H, m, cyclopentyl), 2.21-2.40 (2H, m, CH(CH3)2, H(3)), 2.77 (1H, dd, =7= 7, 16 Hz, CH2CO), 3.04 (1H, dd, =7 = 7, 16 Hz, H(2)), 4.28-4.52 (3H, m, CHCH20); IR (CHC13, cnr1): 2957, 1777, 1699; GC-MS (m/z): 239 (2, M+), 196 (5), 171 (30), 130 (27), 111 (100).…”

Section: Methodsmentioning

confidence: 99%

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Structure-Activity Relationships of Unsaturated Analogs of Valproic Acid

Palaty

Abbott²

1995

J. Med. Chem.

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The principal metabolite of valproic acid (VPA), 2-ene VPA, appears to share most of VPA's pharmacological and therapeutic properties while lacking its hepatotoxicity and teratogenicity, thus making it a useful lead compound for the development of safer antiepileptic drugs. Analogues of 2-ene VPA were evaluated for anticonvulsant activity in mice using the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic acid exhibited a potency markedly exceeding that of VPA itself with only modest levels of sedation. Potency, as either ED50 or brain concentration, was highly correlated (r > 0.85) with volume and lipophilicity rather than with one of the shape parameters calculated by molecular modeling techniques, arguing against the existence of a specific receptor site. Instead, a role for the plasma membrane in mediating the anticonvulsant effect is suggested.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Structure-Activity Relationships of Unsaturated Analogs of Valproic Acid

Palaty

Abbott²

1995

J. Med. Chem.

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“…Therefore, the search for new anticonvulsant drugs continues to be an active area of investigation in medicinal chemistry. [2][3][4][5][6][7][8][9] In a previous paper,10 we reported the synthesis and anticonvulsant properties of new series of 5-substituted benzyl-2-pyridazinylacetamides and 2-pyridazinylacetohydrazides. In view to expand the scope of this investigation to other potential anticonvulsant pyridazine derivatives, we first examined the possibilities to introduce various substituents at the 3-position into the pyridazine ring.…”

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confidence: 99%

Synthesis and Anticonvulsant Properties of New Benzylpyridazine Derivatives

Moreau

Coudert²,

Rubat³

et al. 1994

J. Med. Chem.

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Several 3-substituted pyridazines and a series of imidazo- and triazolopyridazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures in mice. The most active derivatives, 3-ureidopyridazine 7 and triazolopyridazines 16, 18, 21, and 25 with oral ED50's that ranged from 6.2 to 22.0 mg/kg, were more extensively investigated by evaluating their ability to prevent chemically induced seizures and were compared with phenytoin, phenobarbital, sodium valproate, carbamazepine, and diazepam. 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo-[4,3-b]pyridazine (25) was also protective in the pentylenetetrazole-induced seizures test (ED50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED50 = 34.5 mg/kg per os). Furthermore, derivative 25 showed anticonvulsant effects on bicuculline- and yohimbine-induced seizures tests in mice. All these results suggest that the pharmacological activity of 25 is partly due to modifications of glycinergic and GABAergic transmission. Moreover, molecular modeling studies based on the antiepileptic drug lamotrigine and the most stable conformer of 25 show structural similarities between these two molecules. This conformer also agrees with the electronic tolerances and volume of benzodiazepine pharmacophore models.

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Synthesis and Distribution of Tritiated N, N′-dibenzoyl-1,3-diaminopropan-2-ol

Lambert

Gallez

1996

J Label Compd Radiopharm

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Tritiated N,N'-dibenzoyl-l,3-diaminopropan-2-ol, a compound mimicking a diacylglycerol moiety used as a lipid drug carrier was prepared from N,N'-dibenzoyl-l,3-diaminopropan-2-o1 by isotopic exchange in the presence of rhodium chloride. Preliminary preparation of the deuterated analog was made in order to assess the position of the substitution. A biodistribution study was carried out in mice after intravenous administration. Five minutes after administration, the level found in the brain was about 9 % of the injected dose per g organ. This value decreases to 1 % 3 hours after administration while in the same time radioactive levels measured in the urine increased. The results are in accordance with the pharmacological evaluation : N,N'-dibenzoyl-1,3-diaminopropan-2-ol exhibits an anticonvulsant activity at 30 minutes in the maximal electroshock seizure test, but was found inactive at 3 hours.

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Antiepileptic activity of 1,3-dihexadecanoylamino-2-valproyl-propan-2-ol, a prodrug of valproic acid endowed with a tropism for the central nervous system

Cited by 18 publications

References 19 publications

Structure-Activity Relationships of Unsaturated Analogs of Valproic Acid

Structure-Activity Relationships of Unsaturated Analogs of Valproic Acid

Synthesis and Anticonvulsant Properties of New Benzylpyridazine Derivatives

Synthesis and Distribution of Tritiated N, N′-dibenzoyl-1,3-diaminopropan-2-ol

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