Valproic Acid Derivatives Research Articles

Effects of Valproic Acid Derivatives on Inositol Trisphosphate Depletion, Teratogenicity, Glycogen Synthase Kinase-3β Inhibition, and Viral Replication: A Screening Approach for New Bipolar Disorder Drugs Derived from the Valproic Acid Core Structure

Inositol-1,4,5-trisphosphate (InsP3) depletion has been implicated in the therapeutic action of bipolar disorder drugs, including valproic acid (VPA). It is not currently known whether the effect of VPA on InsP3 depletion is related to the deleterious effects of teratogenicity or elevated viral replication, or if it occurs via putative inhibitory effects on glycogen synthase kinase-3beta (GSK-3beta). In addition, the structural requirements of VPA-related compounds to cause InsP3 depletion are unknown. In the current study, we selected a set of 10 VPA congeners to examine their effects on InsP3 depletion, in vivo teratogenic potency, HIV replication, and GSK-3beta activity in vitro. We found four compounds that function to deplete InsP3 in the model eukaryote Dictyostelium discoideum, and these drugs all cause growth-cone enlargement in mammalian primary neurons, consistent with the effect of InsP3 depletion. No relationship was found between InsP3 depletion and teratogenic or elevated viral replication effects, and none of the VPA congeners were found to affect GSK-3beta activity. Structural requirements of VPA congers to maintain InsP3 depletion efficacy greater than that of lithium are a carboxylic-acid function without dependence on side-chain length, branching, or saturation. Noteworthy is the enantiomeric differentiation if a chiral center exists, suggesting that InsP3 depletion is mediated by a stereoselective mode of action. Thus, the effect of InsP3 depletion can be separated from that of teratogenic potency and elevated viral replication effect. We have used this to identify two VPA derivatives that share the common InsP3-depleting action of VPA, lithium and carbamazepine, but do not show the side effects of VPA, thus providing promising novel candidates for bipolar disorder treatment.

Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines

Methylation of tumor suppressor genes is frequently observed in human cancers. These genes are silenced by histone deacetylase (HDAC) recruited by methylated DNA in their promoter regions. HDAC removes acetyl groups from histones and prevents the basic transcriptional machinary access to the target gene, leading to transcriptional repression. HDAC inhibitors (HDACIs) can restore the expression of the tumor suppressor and/or cell cycle regulatory genes in cancer cells and block the cellular proliferation of these cells. In this study, we investigated the in vitro antiproliferative activities of the HDACIs, suberoylanilide hydroxamic acid (SAHA), and valproic acid against 14 human lymphoid cancer cell lines. All of these cell lines were sensitive to the antiproliferative effects of the HDACI. SAHA induced either G1 or G2-M arrest as well as apoptosis. SAHA downregulated cyclin D1 and D2, and upregulated p53, p21, and p27. Chromatin immunoprecipitation analysis revealed a remarkable increase in the level of acetylated histones associated with the p21 promoter after SAHA treatment. In nude mice, SAHA significantly inhibited growth of a mantle cell lymphoma without major toxic side effects. In summary, HDACIs are promising therapeutic agents for human lymphoid cancers.

Traitement d’une dépression résistante par substitution du Dépamide ® par la Dépakine ® chez une patiente avec résection du grêle

Valpromide (VPD) is an antiepileptic drug, derivative of Valproic acid (VPA), used as a mood-stabilizer in bipolar disorder for 25 years in several European countries. VPD is also used as an augmentation strategy in refractory depression. Despite chemical similarity between VPA and VPD, the pharmacokinetics of the 2 drugs in humans are quite distinct. We report a case of a patient, suffering from a bipolar treatment resistant depression, who dramatically improved after substituting VPD to VPA in association with fluoxetine. Mme X, 68 years old, has been hospitalized in March 2001 for the treatment of a resistant depression (TRD). She was suffering from removal of small intestine with chronic diarrhoea after a suicidal attempt two years ago. She had a bipolar disorder treated with VPD (1,200 mg/d) since 1 year. She presented a major depressive episode according to DSM IV with various symptoms like depressed mood, hypersomnia and difficulty initiating sleep, diminished ability to concentrate and to think, markedly diminished pleasure in all activities and major anxiety. Mme X fulfilled TRD diagnosis after resistance to two adequate antidepressants trials from different classes (clomipramine 175 mg/day and venlafaxine 300 mg/day). The antidepressant treatment (venlafaxine) was interrupted and she has been receiving a SSRI (fluoxetine 20 mg/day) for 4 weeks. After four weeks, she had a partial remission with persistent sleep problems, mood lability and anxiety. The VPA blood concentration was very low: 27 mg/L (normal range: 50 to 100 mg/L) in spite of a high dosage: 1,200 mg/day. Pharmacokinetic analysis of VPD shown that VPD transformation to VPA usually done in the intestine, was reduced because of the removal of hail intestine. We substituted VPD by VPA. Valproate blood concentration returned to normal range, induced dramatic improvement of depression within three days. VPD is an amide derivative of valproic acid (valproate), biotransformed by hydrolysis to its corresponding valproic acid. VPD is a prodrug of VPA. VPD is absorbed after transformation in gastro-intestinal mucous membrane. The adequate dosage of VPD (Depamide, 300 mg) is 4 to 6 tablets in acute manic phases, 2 to 4 tablets in long term treatment, 1 to 3 tablets in depressive episode. The biodisponibility of VPD is around 100% 75 and 90% of VPD is linked with protein albumin. The daily dosage determined the blood concentration of the active form (VPA), but this relation isn't linear. The optimal blood concentration of VPA (Depakine) ranges between 50 and 100 mg/L. the free form of VPA is influenced by protein disorders such as of hypoalbuminemia and by presence of fat acids in food. This case report demonstrates at a clinical level that VPD and VPA are not equivalent for treating bipolar depression. This case also suggests that a deep investigation of the pharmacokinetic of psychotropic drugs can help clinicians to resolve clinical problems of treatment of depression.

Differentiation of myeloid leukemia cells by HDAC-inhibitors

Histone deacetylase (HDAC)-inhibitors are a new class of promising anti-cancer agents. Here we show that different structural classes of HDAC-inhibitors (butyric acid, apicidin, MS-275, SAHA, novel synthesized valproic acid derivatives) exhibit anti-proliferative and erythroid differentiation inducing activities in bcr/abl positive K562 myeloid leukemia cells. Inhibition of cell proliferation and erythroid differentiation are accompanied by induction of p21 mRNA and accumulation of hyperacetylated histone H4 proteins in cells. We identified a K562 subline with resistance to erythroid differentiation by HDAC-inhibitors despite evidence of effective HDAC inhibition suggesting that signaling pathways downstream of HDAC-inhibition are defective in these subline. We therefore performed subtractive cDNA-hybridization of K562-sensitive and resistent cells in order to clone genes involved in mediating the HDAC-inhibitor effect in these cells. We identified retinaldehyde-dehydrogenase 2, an enzyme required for intracellular retinoic acid synthesis, as a differentially expressed gene. Treatment of K562 cells with retinoic acid receptor (RAR)-antagonists inhibited erythroid differentiation by HDAC-inhibitors, whereas retinoic acid increased the effect of HDAC-inhibitors on erythroid differentiation.

Teratogenicity of valproate conjugates with anticonvulsant activity in mice

Valproic acid (VPA) is an effective antiepileptic medication, the use of which in females of childbearing age is complicated by its ability to induce birth defects, including neural tube defects (NTDs), in exposed embryos. In experimental settings, VPA reproducibly induces NTDs in laboratory animals such as the highly inbred SWV/Fnn mice. In search of new, efficacious derivatives of VPA that lack toxicity, the conjugates of VPA with amantadine (VPA–AMA) and N-3-aminopropyl-2-pyrrolidinone (VPA–PYR) have been synthesized and evaluated for their anticonvulsant activity. In the present study, the authors evaluated the teratogenicity potential of VPA–AMA and VPA–PYR using a well-established mouse model for antiepileptic drug teratogenicity. All tested compounds were injected intraperitoneally to pregnant dams on gestational day 8.5, and the fetuses examined on day 18.5. At the highest dose tested (3.61 mmol/kg), VPA–PYR was maternally lethal, whereas VPA–AMA induced excessive embryonic lethality. At a dose of 2.20 mmol/kg, VPA–PYR was not teratogenic to the exposed embryos; VPA–AMA induced NTDs in 8.2% of embryos, VPA caused 5.5% NTDs. 0.80 mmol/kg amantadine induced NTDs in 2.2% of the exposed fetuses. In conclusion, VPA–AMA has a comparable teratogenicity as does VPA, and it is proposed that the teratogenicity of VPA–AMA is due to the parent compound. Additional studies are needed to fully define and understand the structure-teratogenicity relationships of VPA analogues.

Reversed-phase high-performance liquid chromatography of polar lipids: II. Procedure for a phospholipid derivative of methotrexate

Phospholipid derivatives of methotrexate (MTX) having enhanced membrane penetration (DP-71 being the most important) are potential prodrugs for treatment of autoimmune and inflammatory diseases as well as diseases involving abnormal cell proliferation. The previously published reversed-phase HPLC methods for similar compounds, phospholipid derivatives of valproic acid and non-steroidal anti-inflammatory drugs (NSAIDs), could not be used for MTX derivatives due to highly basic character of the MTX core molecule. The new HPLC procedure using gradient elution was developed as a compromise between the pharmacopoeial method for MTX and the previous “generic” procedure for phospholipid derivatives of NSAIDs. The newly developed method is sensitive, selective, reproducible, and stability indicating. Identification of major related compounds was carried out. The bioanalytical applications of this method, as well as of the derived isocratic procedure, are discussed and illustrated by examples of pharmacokinetic studies.

New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet?

Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar disorders. The use of VPA is limited by its two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity, and it is the least potent of the established AEDs. Consequently, there is an incentive to develop a second-generation VPA. A successful, second-generation VPA would need to possess the following characteristics: broad-spectrum antiepileptic activity; better potency than VPA; and lack of teratogenicity and hepatotoxicity. These characteristics would give such a drug the potential to be utilized in epilepsy and other CNS disorders. Intensive research has been carried out in order to develop a second-generation VPA that would be more potent and safer than VPA. Amide derivatives of VPA have shown particular value as potential follow-up compounds and have better in-vivo performance than VPA. Several CNS-active valproylamides are more potent as antiepileptics than VPA, they possess broad-spectrum antiepileptic activity, and have been found to be nonteratogenic in animal models. The amide analogues of VPA that emerged from structure-pharmacokinetic-pharmacodynamic relationship studies as promising second-generation compounds are: N-methyl-tetramethylcyclopropane carboxamide, (2S,3S)-valnoctamide, (R)-propylisopropyl acetamide and valproyl glycinamide. At present there are three compounds in clinical trials in patients with epilepsy that can be regarded as second-generation VPA: valproyl glycinamide, 3-methylbutanamide or isovaleramide and SPD421 (DP-VPA). For any one of these second-generation valproic acids to become a successful follow-up compound to VPA, it has to fulfil the above criteria and also possess favorable pharmacokinetics.

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.

Synthesis and Antimicrobial Activities of Some Isocoumarin and Dihydroisocoumarin Derivatives

A new series of the isocoumarin derivatives of ibuprofen, fluribiprofen, naproxen, valproic acid and 1-naphthoic acid have been synthesized via condensation of homophthalic acid with their respective acid chlorides. The conversion of the latter two isocoumarins into ( dl )-3,4-dihydroisocoumarins has also been achieved. Most of the synthesized compounds showed antifungal and antibacterial activities.

Reverse phase HPLC for polar lipids. Simple and selective HPLC procedures for analysis of phospholipid-based derivatives of valproic acid and various non-steroidal anti-inflammatory drugs

DP-VPA (SPD 421) 1 1 Licensing partner: Shire Pharmaceuticals Group plc. is a new compound, where valproic acid is chemically bound to lecithin. It is a novel prodrug of valproic acid with targeted action for the treatment of epilepsy. RP-HPLC stability indicating method has been developed for this and relative compounds. Versatile detection techniques could be used with these LC procedures. The absence of non-volatile components in the mobile phase allows running the method with evaporative light scattering and MS-detectors. The method appeared to be sensitive, selective, reproducible, and stability indicating. It could be easily upgraded to bioanalytical procedures applying LC-MS technique. The method could be used as ‘generic’ for numerous compounds having similar design of the molecules, such as lecithin-based derivatives of diclofenac, naproxen, ibuprofen, and indometacin. The strategy of HPLC method development for polar lipids is discussed.

Peroxisome proliferator-activated receptor δ is a specific sensor for teratogenic valproic acid derivatives

The antiepileptic drug valproic acid (2-propylpentanoic acid) is a potent teratogen in both humans and mice. Valproic acid can induce differentiation of F9 teratocarcinoma cells and stimulate peroxisome proliferator-activated receptor (PPAR) activity. In this study, the structure–activity relationship between valproic acid, its teratogenic and non-teratogenic analogues (branched small- and medium chain fatty acids) and the three PPAR subtypes α, γ or δ was investigated. PPAR-α and PPAR-γ were activated by some valproic acid-derivatives; however, no correlation between teratogenicity and receptor activation could be observed. In contrast, only valproic acid and exclusively its teratogenic analogues were able to activate PPAR-δ in different cellular systems. However, valproic acid appears not to be a direct ligand of PPAR-δ, since in contrast to carbaprostacyclin (cPGI), valproic acid showed not to be able to induce complex formation of PPAR-δ–retinoid X receptor (RXR) heterodimers on DNA. In conclusion, in contrast to PPAR-α and PPAR-γ, PPAR-δ shows to be a specific sensor for teratogenic valproic acid-derivatives.

Stereoselective pharmacokinetic analysis and antiepileptic activity of N-2-hydroxypropyl valpromide, a central nervous system--active chiral valproylamide.

The purpose of this study was to evaluate the anticonvulsant activity and pharmacokinetics (PK) of a novel chiral CNS-active 2-hydroxypropyl valpromide (HP-VPD), a derivative of valproic acid (VPA). The individual enantiomers, R, S, and racemic (R,S)-HP-VPD were synthesized and evaluated for their pharmacokinetics and pharmacodynamics in a stereoselective manner. A stereoselective gas chromatography (GC) assay for simultaneous quantification of HP-VPD enantiomers in plasma and urine was developed and used to investigate the pharmacokinetics of HP-VPD in dogs. Pharmacodynamic analysis in rats showed that (S)-HP-VPD was 2.5 times more potent as an anticonvulsant in the maximal electroshock seizure (MES) test than its enantiomer and approximately 10 times more potent than VPA. No significant differences were observed in major PK parameters (clearance, volume of distribution, and half-life) between S and (R)-HP-VPD, and this suggested that pharmacodynamic differences could be attributed to the intrinsic pharmacodynamics of each enantiomer rather than to a preferable pharmacokinetic profile. The pharmacokinetic (metabolic) analysis showed that the fraction metabolized to HP-VPD-glucuronide ranged from 5% to 7% and no biotransformation of HP-VPD to VPA and 2-ketopropyl valpromide was observed. This is the first report of significant stereoselectivity in the anticonvulsant activity of a valproylamide with a chiral carbon situated on the alkyl chain of the amine moiety.

Induction of differentiation in F9 cells and activation of peroxisome proliferator-activated receptor delta by valproic acid and its teratogenic derivatives.

The antiepileptic drug valproic acid (VPA) is teratogenic, because it induces birth defects in some children of mothers treated for epilepsy. Cellular and molecular actions associated with teratogenicity were identified by testing differentiation of F9 embryocarcinoma cells. VPA altered cell morphology and delayed proliferation. Specific differentiation markers (e.g., c-fos and keratin 18 mRNA and particularly the activating protein-2 transcription factor protein) were induced. This pattern differs from the pattern induced by other teratogens or F9 cell-differentiating agents. Induction of differentiation correlated with teratogenicity because teratogenic derivatives of VPA, such as (S)-4-yn-VPA, induced differentiation, whereas closely related nonteratogenic compounds, such as (R)-4-yn-VPA, 2-en-VPA, and 4-methyl-VPA, did not. In the cellular signaling network, the peroxisome proliferator-activated receptor delta (PPARdelta) was activated selectively by VPA and teratogenic derivatives. Depletion of PPARdelta by antisense RNA expression precluded the response of F9 cells to VPA. In conclusion, our data show that VPA and its teratogenic derivatives induce a specific type of F9 cell differentiation and that PPARdelta is a limiting factor in the control of differentiation.

Synthesis of valproic acid amides of a melatonin derivative, a piracetam and amantadine for biological tests.

Three new amide derivatives of valproic acid have been synthesized and characterized by spectrophotometric studies. The rationale for the preparation of such agents has been based on the observation that chemical combination of the anticonvulsant pharmacophore, valproic acid with amine moieties produces more effective and less toxic amides. The amine components selected in this work also exhibit neuroactivity with the prospect of these agents being biologically active in controlling not just seizures and but also possessing neuroprotective properties. We report here the synthesis and properties of the valproylamides of 5-methoxytryptamine, related to melatonin (1), of N-substituted 2-pyrrolidinone related to piracetam (2), and of adamantylamine related to amantadine (3). In preliminary tests these compounds showed low toxicity and a variety of anticonvulsive properties, including a delay in onset of activity. These compounds and their derivatives are now available to be tested additionally for control of subclinical seizures, enhancement of cognition, behavior modification and alleviation of symptoms and disorders due to neuronal damage.

Research on the pharmacochemistry of some GABA and valproic acid derivatives

The role of GABA in epilepsy and especially in the action of various antiepileptics has been well established. We have reported the synthesis and pharmacochemical evaluation of a number of GABA and valproic acid derivatives and also the synthesis of two N-acyl-2-pyrrolidinone derivatives. We now report the pharmacochemical evaluation—anticonvulsant and antioxidant activity, and also study of lipophilicity—of the latter two in combination with the synthesis and evaluation of two novel ester derivatives (2-propylpentyl-3-pyridine carboxylate and 3-pyridinylmethyl 2-propylpentanoate), which contain the moieties of valproic acid and of 2-propyl-1-pentanol. Anticonvulsant activity was evaluated using the picrotoxin model and the antioxidant potential using the lipid peroxidation method. The study of lipophilicity was performed both by experimental (by reversed phase thin layer chromatography) and calculating (Rekker’s and Hansch/Leo’s fragmental and Suzuki/Kudo’s atom-based) methods; lipophilicity was also studied in combination with other physicochemical parameters of the above-mentioned compounds (van der Waals volume, van der Waals area, dipole moment, energy of formation, energy of hydration). In this study, we also include six other derivatives which we synthesized and tested in an earlier study. Only the two ester derivatives exhibited potent anticonvulsant and also antioxidant activity; the 2-pyrrolidinones did not exhibit significant activity in these experiments. In accordance with our earlier findings, the nicotinoyl and the nicotinyl moieties, in combination with considerable lipophilicity, seem to be suitable groups to confer activity in this type of compound. Good multiple correlation was derived between lipophilicity and energy of hydration and van der Waals volume of the compounds. Drug Dev. Res. 51:143–148, 2000. © 2001 Wiley-Liss, Inc.

Research on the pharmacochemistry of some GABA and valproic acid derivatives

The role of GABA in epilepsy and especially in the action of various antiepileptics has been well established. We have reported the synthesis and pharmacochemical evaluation of a number of GABA and valproic acid derivatives and also the synthesis of two N-acyl-2-pyrrolidinone derivatives. We now report the pharmacochemical evaluation—anticonvulsant and antioxidant activity, and also study of lipophilicity—of the latter two in combination with the synthesis and evaluation of two novel ester derivatives (2-propylpentyl-3-pyridine carboxylate and 3-pyridinylmethyl 2-propylpentanoate), which contain the moieties of valproic acid and of 2-propyl-1-pentanol. Anticonvulsant activity was evaluated using the picrotoxin model and the antioxidant potential using the lipid peroxidation method. The study of lipophilicity was performed both by experimental (by reversed phase thin layer chromatography) and calculating (Rekker’s and Hansch/Leo’s fragmental and Suzuki/Kudo’s atom-based) methods; lipophilicity was also studied in combination with other physicochemical parameters of the above-mentioned compounds (van der Waals volume, van der Waals area, dipole moment, energy of formation, energy of hydration). In this study, we also include six other derivatives which we synthesized and tested in an earlier study. Only the two ester derivatives exhibited potent anticonvulsant and also antioxidant activity; the 2-pyrrolidinones did not exhibit significant activity in these experiments. In accordance with our earlier findings, the nicotinoyl and the nicotinyl moieties, in combination with considerable lipophilicity, seem to be suitable groups to confer activity in this type of compound. Good multiple correlation was derived between lipophilicity and energy of hydration and van der Waals volume of the compounds. Drug Dev. Res. 51:143–148, 2000. © 2001 Wiley-Liss, Inc.

Structure activity relationship of human microsomal epoxide hydrolase inhibition by amide and acid analogues of valproic acid.

The purpose of this study was to evaluate the in vitro inhibitory potency of various amide analogues and derivatives of valproic acid toward human microsomal epoxide hydrolase (mEH). mEH inhibition was evaluated in human liver microsomes with 25 microM (S)-(+)-styrene oxide as the substrate. Inhibitory potency expressed as the median inhibitory concentration (IC50) was calculated from the formation rate of the enzymatic product, (S)-(+)-1-phenyl-1,2-ethanediol. Inhibitory potency was directly correlated with lipophilicity and became significant for amides with a minimum of eight carbon atoms. Branched eight-carbon amides were more potent inhibitors than their straight chain isomer, octanamide. N-substituted valproylamide analogues had reduced or abolished inhibition potency with the exception of valproyl hydroxamic acid being a potent inhibitor. Inhibition potency was not stereoselective in two cases of chiral valpromide isomers. Valproyl glycinamide, a new antiepileptic drug currently undergoing phase II clinical trials and its major metabolite valproyl glycine were weak mEH inhibitors. Acid isomers of valproic acid were not potent mEH inhibitors. The structural requirements for valproylamide analogues for potent in vitro mEH inhibition are: an unsubstituted amide moiety; two saturated alkyl side chains; a minimum of eight carbons in the molecule.

Pharmacokinetic considerations in the design of better and safer new antiepileptic drugs

Valproic acid (VPA) is one of the major antiepileptic drugs. However, its anticonvulsant potency is less than the other three major antiepileptic drugs. Furthermore, VPA causes two rare but severe side effects: teratogenicity and hepatotoxicity. We utilized pharmacokinetic considerations in designing various amide derivatives of VPA which are more potent as anticonvulsants than VPA and have the potential to be nonteratogenic and nonhepatotoxic. The following three groups of VPA derivatives were designed and evaluated: (1) Isomers of valpromide (VPD) in order to explore the structural requirements for metabolically stable VPD isomers. Two chiral amides, valnoctamide and propylisopropyl acetamide, have emerged from a stereospecific study as the optimal compounds; (2) Cyclic amide derivatives of VPD. N-Methyl 2,2,3,3-tetramethylcyclopropane carboxamide (M-TMCD) was found to be the optimal compound in this series. M-TMCD is a stable achiral VPD analogue acid which is nonteratogenic. Since M-TMCD contains four methyl substituents it cannot form a metabolite with a terminal double bond, and thus has the potential to be a nonhepatotoxic compound; (3) Conjugation products of VPA and γ-amino butyric acid (GABA) or glycine. N-valproyl glycinamide (VGD) emerged as the best compound out of this group and is currently undergoing phase II clinical trials. VGD is mainly metabolized to N-valproyl glycine by a nonoxidative hydrolytic metabolic pathway. It did not operate as chemical drug delivery systems of VPA and glycine or GABA, but acted rather as a drug on its own.

Effects of new valproate derivatives on epileptiform discharges induced by pentylenetetrazole or low Mg2+ in rat entorhinal cortex-hippocampus slices.

The effects of four valproic acid derivatives were studied on pentylenetetrazole-induced epileptiform discharges in combined entorhinal cortex hippocampus slices. The two new sugar-esters of valproic acid, dimethylenexylitol valproate (VDMX, 0.5 mM) and glucose valproate (VG, 2 mM) abolished the epileptiform activity. These two new derivatives were compared to two clinically used anticonvulsant drugs, valpromide (2 mM) which suppressed the activity and valproic acid (2 mM), which was ineffective. The new drugs VDMX and VG were also tested on different patterns of epileptiform activity induced by lowering of [Mg2+]0. A 1 mM concentration of VDMX and 2 mM VG, reversibly suppressed the recurrent short discharges in area CA1 and the seizure-like events in the entorhinal cortex. A concentration of 2 mM VDMX was required to abolish the late recurrent discharges in entorhinal cortex. VG at 2 mM reduced the frequency of these discharges by 58.5+/-9.5%.

P3G184 - New molecular bioassay based on cell differentiation in vitro for the estimation of the teratogenic potency of valproic acid derivatives

The gas permeation behavior of 2,2′-bis(3,4′dicarboxyphenyl) hexafluoropropane dianhydride(6FDA)-2,4,6-trimethyl-1,3-phenylenediamine (TMPDA)/4,4′-methylene bis(2-chloroaniline) (MOCA) copolyimides was investigated by systematically varying the diamine ratios. All the copolyimides were soluble in most of the common solvents. The gas permeabilities and diffusion coefficients decreased with increasing MOCA content; however, the permselectivity of gas pairs such as H2/N2, O2/N2, CO2/CH4 was enhanced with the incorporation of MOCA moiety. Moreover, all of the copolyimides studied in this work exhibited performance near, lying on or above the existing upper bound trade-off line between permselectivity and permeability.