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  • 1
    Electronic Resource
    Electronic Resource
    Structure–Pharmacokinetic Relationships in a Series of Valpromide Derivatives with Antiepileptic Activity (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 683-689 
    Details
    ISSN: 1573-904X
    Keywords: valpromide ; valproic acid ; antiepileptic activity ; SAR ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The following valpromide (VPD) derivatives were synthesized and their structure–pharmacokinetic relationships explored: ethylbutylacetamide (EBD), methylpentylacetamide (MPD), propylisopropylacetamide (PID), and propylallylacetamide (PAD). In addition, the anticonvulsant activity of these compounds was evaluated and compared to that of VPD, valnoctamide (VCD), and valproic acid (VPA). MPD, the least-branched compound had the largest clearance and shortest half-life of all the amides investigated and was the least active. All other amides had similar pharmacokinetic parameters. Unlike the other amides, PID and VCD did not metabolize to their respective homologous acids and were the most active compounds. Our study showed that these amides need an unsubstituted β position in their aliphatic side chain in order to biotransform to their homologous acids. An amide which is not metabolized is more potent as an anticonvulsant than its biotransformed isomer. All amides were more active than their respective homologous acids. In this particular series of aliphatic amides, which were derived from short-branched fatty acids, the anticonvulsant activity was affected by the pharmacokinetics in general and by the biotransformation of the amide to its homologous acid in particular. This amide–acid biotransformation appeared to be dependent upon the chemical structure, especially upon the substitution at position β of the molecule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015934321764
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 284-289 
    Details
    ISSN: 1573-904X
    Keywords: valproic acid ; valpromide ; tetramethylcyclopropane derivatives ; pharmacokinetics ; antiepileptic activity ; structural requirements
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the β position to the carbonyl, such as in the case of TMCD, or a substitution in the α and in the β positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016055517724
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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