Structure–pharmacokinetic relationships in a series of short fatty acid amides that possess anticonvulsant activity

Valpromide (VPD) and valnoctamide (VCD) are two isomers which are aliphatic amides derived from short fatty acids that possess anticonvulsant activity. Our previous studies with VPD, VCD, and other related compounds showed that the biotransformation of these amides to their respective homologous acids is the key issue in their possessing pharmacological activity. In this study, we explored the structure–pharmacokinetic relationships of the following five isomers or analogues of VPD: diisproprylacetamide (DID), diallylacetamide (DAD), octanamide (OAD), ethylisobutylacetamide (EID), and dimethylbutylacetamide (DBD). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPD and VCD. No plasma levels of OAD could be detected after its iv administration. Octanamide (OAD) was very rapidly metabolized to its homologous acid, octanoic acid (OAA). Octanamide (OAD) was different from the other four amides investigated, having a high clearance (due to metabolic processes in the blood) and possessing the least anticonvulsant activity. All of the other amides were stable in blood and showed similar pharmacokinetic parameters. Unlike the other amides, DID and VCD did not metabolize to their respective homologous acids due to the fact that they had a substituted β position in their aliphatic side chain. Our study showed that, despite similarities in the chemical structures of the amides investigated, significant differences were observed in their pharmacokinetics and in the fraction of the amide (f_m) biotransformed to its homologous acid. These differences in f_m values may, therefore, account for the observed differences in the respective pharmacological activities, in general, and in the extent of the anticonvulsant activity, in particular, of the amides. In this particular series of aliphatic amides, which were derived from short‐branched fatty acids, the biotransformation of the amide to its homologous acid appeared dependent on the chemical structure, especially on the substitution at the β position of the molecule.