sec-butyl-propylacetamide and valnoctamide

sec-Butylpropylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide--valpromide. Racemic-SPD and racemic-VCD possess a unique and broad-spectrum antiseizure profile superior to that of VPA. In addition, SPD blocks behavioral and electrographic status epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamide has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset. sec-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model. sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (2S,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,3S)-VCD exhibiting the lowest clearance and, consequently, a twice-higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".

Topics: Amides; Animals; Anticonvulsants; Humans; Status Epilepticus; Stereoisomerism; Valproic Acid

Valnoctamide (VCD) and sec-butylpropylacetamide (SPD) are CNS-active closely related amide derivatives of valproic acid with unique anticonvulsant activity. This study evaluated how small chemical changes affect the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetics (PK) of three constitutional isomers of SPD [sec-butylisopropylacetamide (SID) and tert-butylisopropylacetamide (TID)] and of VCD [tert-butylethylacetamide (TED)]. The anticonvulsant activity of SID, TID, and TED was comparatively evaluated in several rodent anticonvulsant models. The PK-PD relationship of SID, TID, and TED was evaluated in rats, and their teratogenicity was evaluated in a mouse strain highly susceptible to teratogen-induced neural tube defects (NTDs). sec-Butylisopropylacetamide and TID have a similar PK profile to SPD which may contribute to their similar anticonvulsant activity. tert-Butylethylacetamide had a better PK profile than VCD (and SPD); however, this did not lead to a superior anticonvulsant activity. sec-Butylisopropylacetamide and TED did not cause NTDs at doses 4-7 times higher than their anticonvulsant ED50 values. In rats, SID, TID (ip), and TED exhibited a broad spectrum of anticonvulsant activity. However, combined anticonvulsant analysis in mice and rats shows SID as the most potent compound with similar activity to that of SPD, demonstrating that substitution of the isobutyl moiety in the SPD or VCD molecule by tert-butyl as well as a propyl-to-isopropyl replacement in the SPD molecule did not majorly affect the anticonvulsant activity.

Topics: Amides; Animals; Anticonvulsants; Female; Isomerism; Male; Mice; Mice, Transgenic; Rats; Rats, Sprague-Dawley; Seizures; Valproic Acid

sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20-60 min after seizure onset. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20-60 min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .

Topics: Acute Disease; Amides; Animals; Anticonvulsants; Disease Models, Animal; Guinea Pigs; Humans; Rats; Seizures; Status Epilepticus; Treatment Outcome; Valproic Acid

To determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma (HepG2) cells, and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSRs) to other medication.. Cells were exposed to physiological doses of VPA, valnoctamide (VCD) and its one carbon homologue sec-Butyl-propyl-acetamide (SPD) for 2h and for 24h. Cell viability was measured using succinate dehydrogenase activity for hepatocytes and lymphocyte toxicity assay (LTA) for lymphocytes. Cytokines and apoptosis [cytokeratine 18 (cCK18-M30)] markers were quantitated by ELISA.. VCD and SPD presented lower cytotoxicity compared to VPA in cultured HepG2 cells. SPD led to cytotoxicity in lymphocytes. VPA and its derivatives increased the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in media, but had no influence on the release of either interleukin (IL)-1 or IL-6. Significant increases in the release of IFN-γ and TNF-α were observed in lymphocytes exposed to high doses of VPA, and this increased further with exposure time.. HepG2 cells exposed to VCD and SPD experienced lower direct cytotoxicity than those treated with VPA. Lymphocytes from patients that experienced HSR to other medication have shown cytotoxicity to VPA and its VPA derivatives-induced. High levels of pro-inflammatory cytokines were released in the cell culture media, suggesting that inflammation plays a key role in VPA-derivatives induced lymphocyte toxicity.

Topics: Amides; Apoptosis; Cell Line, Tumor; Cell Survival; Cells, Cultured; DNA Repair; Drug Hypersensitivity Syndrome; Gene Expression; Hepatocytes; Humans; Inflammation; Interferon-gamma; Interleukin-1; Interleukin-6; Keratin-18; Lymphocytes; Signal Transduction; Tumor Necrosis Factor-alpha; Valproic Acid

Better treatment of status epilepticus (SE), which typically becomes refractory after about 30 min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. Using a previously-published algorithm, the effects of SPD on ESE were compared quantitatively to other relevant compounds. To confirm benzodiazepine resistance, diazepam (DZP) was shown to suppress ESE when administered 15 min after the first motor seizure, but not after 30 min (100mg/kg). VPA (300 mg/kg) also lacked efficacy at 30 min. SPD (130 mg/kg) strongly suppressed ESE at 30 min, less after 45 min, and not at 60 min. At a higher dose (180 mg/kg), SPD profoundly suppressed ESE at 60 min, similar to propofol (100mg/kg) and pentobarbital (30 mg/kg). After 4-6h of SPD-induced suppression, EEG activity often overshot control levels at 7-12h. Valnoctamide (VCD, 180 mg/kg), an SPD homolog, was also efficacious at 30 min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1h after the first motor seizure. SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.

Topics: Amides; Animals; Anticonvulsants; Cerebral Cortex; Diazepam; Dose-Response Relationship, Drug; Electroencephalography; Male; Pentobarbital; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus; Valproic Acid

sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death.. The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s.c.) metrazol-, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model.. SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD(50)/ED(50)]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED(50) for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine-induced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED(50) values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/L (40 min after the onset of soman-induced seizures). The time to peak (t(max)) pharmacodynamic effect (PD-t(max)) occurred after the PK-t(max), suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD.. The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.

Topics: Amides; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Hippocampus; Male; Mice; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Time Factors; Treatment Outcome; Valproic Acid