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  • 1
    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
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    Paper (German National Licenses)
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  • 2
    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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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Analysis of the Structural Requirements for Forming “Stable” Analogues of Valpromide (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1058-1063 
    Details
    ISSN: 1573-904X
    Keywords: valpromide ; stable analogues ; pharmacokinetics ; structural requirements
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be “stable” to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the β position of its chemical structure. A “stable” valpromide analogue must have either two substitutions at the β position, such as in the case of TBD, or a substitution in the α and β positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015862613315
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Anticonvulsant Activity of Three Monoesteric Prodrugs of Valproic Acid (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 750-753 
    Details
    ISSN: 1573-904X
    Keywords: valproic acid ; esteric prodrugs ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of valproic acid (VPA) were compared in dogs with those of the prodrugs ethyl valproate (E-VPA), trichloroethyl valproate (T-VPA), and valproyl valproate (V-VPA). Valproic acid, E-VPA, T-VPA, and V-VPA were administered intravenously and orally to six dogs at equimolar doses. The three VPA prodrugs were rapidly converted to VPA. The biotransformation was complete in the case of E-VPA and T-VPA but was only partial in the case of V-VPA. Because of the rapid conversion to the parent drug, after administration of the prodrugs, VPA plasma levels did not yield a sustained-release profile. Further, the anticonvulsant activity of prodrugs was compared in mice to that of VPA and valpromide (VPD). The anticonvulsant activity of E-VPA, T-VPA, and V-VPA was less than that of VPA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015854118110
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  • 5
    Electronic Resource
    Electronic Resource
    Structure Activity Relationship of Human Microsomal Epoxide Hydrolase Inhibition by Amide and Acid Analogues of Valproic Acid (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 216-221 
    Details
    ISSN: 1573-904X
    Keywords: microsomal epoxide hydrolase inhibition ; valnoctamide ; valpromide analogues ; valproic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to evaluate the in vitro inhibitory potency of various amide analogues and derivatives of valproicacid toward human microsomal epoxide hydrolase (mEH). Methods. mEH inhibition was evaluated in human liver microsomeswith 25 μ (S)-(+)-styrene oxide as the substrate. Inhibitory potencyexpressed as the median inhibitory concentration (IC50) was calculatedfrom the formation rate of the enzymatic product,(S)-(+)-1-phenyl-1,2-ethanediol. Results. Inhibitory potency was directly correlated with lipophilicityand became significant for amides with a minimum of eight carbonatoms. Branched eight-carbon amides were more potent inhibitors thantheir straight chain isomer, octanamide. N-substituted valproylamideanalogues had reduced or abolished inhibition potency with theexception of valproyl hydroxamic acid being a potent inhibitor. Inhibitionpotency was not stereoselective in two cases of chiral valpromideisomers. Valproyl glycinamide, a new antiepileptic drug currentlyundergoing phase II clinical trials and its major metabolite valproylglycine were weak mEH inhibitors. Acid isomers of valproic acid werenot potent mEH inhibitors. Conclusions. The structural requirements for valproylamide analoguesfor potent in vitro mEH inhibition are: an unsubstituted amide moiety;two saturated alkyl side chains; a minimum of eight carbons in themolecule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007577600088
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