3116-29-8Relevant articles and documents
α-Linolenic Acid-Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis
Rossi, Michele,Petralla, Sabrina,Protti, Michele,Baiula, Monica,Kobrlova, Tereza,Soukup, Ondrej,Spampinato, Santi Mario,Mercolini, Laura,Monti, Barbara,Bolognesi, Maria Laura
supporting information, p. 2406 - 2413 (2020/11/16)
Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of α-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways.
Pharmacokinetics and antiepileptic activity of valproyl hydroxamic acid derivatives
Levi, Micha,Yagen, Boris,Bialer, Meir
, p. 213 - 217 (2007/10/03)
Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. Results. Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid - VPA-HA, N-(1-hydroxyethyl)-valpromide-HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(1-methoxyethyl) valpromide and N-(1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the 'active compounds VPA-HA and HEV was studied. Conclusions. In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant vaIproyl hydroxamic acid derivatives.