sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid for the treatment of neuropathic and inflammatory pain.

Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world's population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD's activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.

sec-Butylpropylacetamide (SPD) has antimigraine properties.

BACKGROUND: Though migraine is disabling and affects 12%-15% of the population, there are few drugs that have been developed specifically for migraine prevention. Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that is also used for migraine prophylaxis, but its clinical use is limited by its side effect profile. sec-Butylpropylacetamide (SPD) is a novel VPA derivative, designed to be more potent and tolerable than VPA, that has shown efficacy in animal seizure and pain models. METHODS: We evaluated SPD's antimigraine potential in the cortical spreading depression (CSD) and nitroglycerin (NTG) models of migraine. To evaluate SPD's mechanism of action, we performed whole-cell recordings on cultured cortical neurons and neuroblastoma cells. RESULTS: In the CSD model, the SPD-treated group showed a significantly lower median number of CSDs compared to controls. In the NTG-induced mechanical allodynia model, SPD dose-dependently reduced mechanical sensitivity compared to controls. SPD showed both a significant potentiation of GABA-mediated currents and a smaller but significant decrease in NMDA currents in cultured cortical neurons. Kainic acid-evoked currents and voltage-dependent sodium channel currents were not changed by SPD. CONCLUSIONS: These results demonstrate SPD's potential as a promising novel antimigraine compound, and suggest a GABAergic mechanism of action.

The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus.

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".

Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS-active derivative of valproic acid with low teratogenic potential.

OBJECTIVE: Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. METHODS: The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. RESULTS: VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3-12 times higher than VCD anticonvulsant ED50 values. SIGNIFICANCE: VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs.

Valnoctamide and sec-butyl-propylacetamide (SPD) for acute seizures and status epilepticus.

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 .

Teratology study of amide derivatives of branched aliphatic carboxylic acids with 4-aminobenzensulfonamide in NMRI mice.

BACKGROUND: Valproic acid (VPA), widely used to treat epilepsy, bipolar disorders, and migraine prophylaxis, is known to cause neural tube and skeletal defects in humans and animals. Aminobenzensulfonamide derivatives of VPA with branched aliphatic carboxylic acids, namely 2-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (MSP), 2-ethyl-N-(4-sulfamoyl-phenyl)-butyramide (ESB), 2-ethyl-4-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (EMSP), and 2-ethyl-N-(4-sulfamoyl-benzyl)-butyramide (ESBB), have shown more potent anticonvulsant activity than VPA in preclinical testing. Here, we investigated the teratogenic effects of these analogous compounds of VPA in NMRI mice. METHODS: Pregnant NMRI mice were given a single subcutaneous injection of either VPA at 1.8 or 3.6 mmol/kg, or MSP, ESB, EMSP, or ESBB at 1.8, 3.6, or 4.8 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18, and the live fetuses were examined for external and skeletal malformations. RESULTS: Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at dose levels up to 4.8 mmol/kg (except for a single case of exencephaly at 4.8 mmol/kg MSP). Skeletal examination showed several abnormalities mainly at the axial skeletal level with VPA at 1.8 mmol/kg. Fused vertebrae and/or fused ribs were also observed with MSP, ESB, EMSP, and ESBB, they were less severe and seen at a lower incidence that those induced by VPA at the same dose level. CONCLUSIONS: In addition to exerting more potent preclinical antiepileptic activity, teratology comparison indicates that aminobenzensulfonamide analogs are generally more weakly teratogenic than VPA.

A new derivative of valproic acid amide possesses a broad-spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage.

PURPOSE: 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. METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.

Design and pharmacological activity of glycinamide and N-methoxy amide derivatives of analogs and constitutional isomers of valproic acid.

A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED(50) values of N-methoxy-VCD were 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol test), and 35 mg/kg (6-Hz test), and its neurotoxicity TD(50) was 118 mg/kg. In rats, the ED(50) of N-methoxy-VCD in the subcutaneous metrazol test was 36 mg/kg and its protective index (PI=TD(50)/ED(50)) was >5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED(50) values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug.

Evaluation of stereoselective anticonvulsant, teratogenic, and pharmacokinetic profile of valnoctylurea (capuride): a chiral stereoisomer of valproic acid urea derivative.

PURPOSE: The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)-active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA). METHODS: VCU stereoisomers (2S,3S)-VCU and (2R,3S)-VCU were synthesized. Their anticonvulsant activity was determined and compared to VPA and racemic-VCU in rats utilizing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scMet) tests. Neurotoxicity was determined in rats using the positional sense test, muscle tone test, and gait and stance test. The induction of neural tube defects (NTDs) by VCU stereoisomers was evaluated in a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of VCU was studied in a stereoselective manner following intraperitoneal (i.p.) administration to rats. RESULTS: (2S,3S)-VCU and (2R,3S)-VCU median effective dose ED(50) values were 29 mg/kg [95% confidence interval (CI) = 8-60 mg/kg] and 42 mg/kg (95% CI = 36-51 mg/kg) (MES) and 22 mg/kg (95% CI = 13-51 mg/kg) and 12 mg/kg (95%CI = 7-21 mg/kg) (scMet), respectively. (2S,3S)-VCU was more potent and had a wider safety margin (p < 0.05), defined as the protective index (PI = TD(50)/ED(50)), at both the MES (PI > 17) and scMet (PI > 23) tests than racemic-VCU or (R,S)-VCU (PI = 2.8 and 9.9, respectively). VCU stereoisomers caused NTDs at doses >4 times that of their anticonvulsant ED(50) values. At a dose of 112 mg/kg, (2R,3S)-VCU was nonteratogenic and less embryotoxic than its stereoisomer (2S,3S)-VCU. No stereoselective pharmacokinetics was observed following intraperitoneal dosing of racemic-VCU to rats. VCU was mainly eliminated by metabolism with a half-life of 2 h. CONCLUSIONS: VCU anticonvulsant activity and wide PI values make it a potential candidate for development as a new, potent antiepileptic drug (AED).

Comparative pharmacodynamic and pharmacokinetic analysis of two anticonvulsant halo derivatives of 2,2,3,3-tetramethylcyclopropanecarboxamide, an amide of a cyclic analog of valproic acid.

PURPOSE: α-Fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide (α-F-TMCD) and α-Cl-TMCD, are α-halo derivatives of TMCD, the corresponding amide of a cyclopropane analog of valproic acid (VPA). This study aimed to comparatively evaluate the pharmacodynamics and pharmacokinetics of α-F-TMCD and α-Cl-TMCD in rodent models of epilepsy and for antiepileptic drug (AED)-induced teratogenicity. The potential of α-F-TMCD as an antiallodynic and antinociceptive compound was also evaluated. METHODS: α-F-TMCD and α-Cl-TMCD were synthesized. α-Cl-TMCD anticonvulsant activity was evaluated in comparison to VPA in the mouse maximal-electroshock-seizure (MES), Metrazol (scMet), and 6-Hz psychomotor-seizure tests. Neurotoxicity was assessed by the Rotorod-ataxia test. Induction of neural tube defects (NTDs) by α-Cl-TMCD and α-F-TMCD was evaluated after intraperitoneal administration to a mouse strain highly susceptible to VPA-induced teratogenicity. The ability of α-F-TMCD to reduce pain was evaluated in the rat spinal nerve ligation (SNL) model for neuropathic pain and in the formalin test. α-F-TMCD and α-Cl-TMCD pharmacokinetics was evaluated following intraperitoneal (40 mg/kg) and oral (60 mg/kg) administration to rats. RESULTS: α-F-TMCD and α-Cl-TMCD had similar potencies in the 6-Hz test and were more potent than VPA in this model and in the scMet test. Neither induced NTDs, and both exhibited wide safety margins. α-F-TMCD was active in the two pain models, and was found to be equipotent to gabapentin in the SNL model (ED(50) = 37 and 32 mg/kg, respectively). Comparative pharmacokinetic analysis showed that α-Cl-TMCD is less susceptible to liver first-pass effect than α-F-TMCD because of lower total (metabolic) clearance and liver extraction ratio. CONCLUSIONS: Based on their potent anticonvulsant activity and lack of teratogenicity, α-F-TMCD and α-Cl-TMCD have the potential for development as new antiepileptics and central nervous system (CNS) drugs.

Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice.

BACKGROUND: Valproic acid (VPA) is used to treat epilepsy and bipolar disorders, as well as for migraine prophylaxis. However, its clinical use is limited by two life-threatening side effects: hepatotoxicity and teratogenicity. To develop a more potent and safer second-generation VPA drug, the urea derivatives of four VPA analogs (2-ethyl-3-methylpentanoyl urea, 2-ethylhexanoyl urea, 2-ethyl-4-methylpentanoyl urea, and 2-methylbutanoyl urea) were synthesized. METHODS: Four CNS-active analogs of a VPA urea derivative testedthe anticonvulsant activity in the maximal electroshock seizure test (MES) and subcutaneous metrazol seizure threshold test (scMet). Teratogenic effects of these compounds were evaluated in NMRI mice susceptible to VPA-induced teratogenicity by comparison with VPA. RESULTS: All four VPA analogs showed superior anticonvulsant activity over VPA. Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at any concentration up to 4.8 mmol/kg (except for a single abnormality at 3.6 mmol/kg with 2-ethyl-3-methylpentanoyl urea). Skeletal examination also revealed that the acylurea derivatives induced vertebral and rib abnormalities in fetuses markedly less frequently than VPA. Our results confirmed that the analogue derivatives are significantly less teratogenic than VPA in NMRI mice. CONCLUSIONS: The CNS-active VPA analogs containing a urea moiety, which have better anticonvulsant potency and lack teratogenicity, are good potential candidates as second-generation VPA antiepileptic drugs.

Evaluation of the enantioselective antiallodynic and pharmacokinetic profile of propylisopropylacetamide, a chiral isomer of valproic acid amide.

Propylisopropylacetamide (PID) is a chiral CNS-active constitutional isomer of valpromide, the amide derivative of the major antiepileptic drug valproic acid (VPA). The purpose of this work was: a) To evaluate enantiospecific activity of PID on tactile allodynia in the Chung (spinal nerve ligation, SNL) model of neuropathic pain in rats; b) To evaluate possible sedation at effective antiallodynic doses, using the rotorod ataxia test; c) To investigate enantioselectivity in the pharmacokinetics of (R)- and (S)-PID in comparison to (R,S)-PID; and d) To determine electrophysiologically whether PID has the potential to affect tactile allodynia by suppressing ectopic afferent discharge in the peripheral nervous system (PNS). (R)-, (S)- and (R,S)-PID produced dose-related reversal of tactile allodynia with ED(50) values of 46, 48, 42 mg/kg, respectively. The individual PID enantiomers were not enantioselective in their antiallodynic activity. No sedative side-effects were observed at these doses. Following i.p. administration of the individual enantiomers, (S)-PID had lower clearance (CL) and volume of distribution (V) and a shorter half-life (t(1/2)) than (R)-PID. However following administration of (R,S)-PID, both enantiomers had similar CL and V, but (R)-PID had a longer t(1/2). Systemic administration of (R,S)-PID at antiallodynic doses did not suppress spontaneous ectopic afferent discharge generated in the injured peripheral nerve, suggesting that its antiallodynic action is exerted in the CNS rather than the PNS. Both of PID's enantiomers, and the racemate, are more potent antiallodynic agents than VPA and have similar potency to gabapentin. Consequently, they have the potential to become new drugs for treating neuropathic pain.

Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a potential for a second generation drug to valproic acid.

PURPOSE: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential second-generation drugs to valproic acid (VPA). METHODS: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. RESULTS: DBU emerged as the most potent compound having an MES-ED(50)of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED(50)of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED(50)= 35 mg/kg), the psychomotor 6 Hz mouse model (ED(50)= 80 mg/kg at 32 mA and ED(50)= 133 mg/kg at 44 mA), the bicuculline- and picrotoxin-induced seizure mouse model (ED(50)= 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half-life of 4.5 h. CONCLUSIONS: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.

Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: evaluation of the teratogenic effects of its amide derivatives in NMRI mice.

BACKGROUND: Although valproic acid (VPA) is used extensively for treating various kinds of epilepsy, it causes hepatotoxicity and teratogenicity. In an attempt to develop a more potent and safer second generation to VPA drug, the amide derivatives of the tetramethylcyclopropyl VPA analogue, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD), N-methyl-TMCD (MTMCD), 4-(2,2,3,3-tetramethylcyclopropanecarboxamide)-benzenesulfonamide (TMCD-benzenesulfonamide), and 5-(TMCD)-1,3,4-thiadiazole-2-sulfonamide (TMCD-thiadiazolesulfonamide) were synthesized and shown to have more potent anticonvulsant activity than VPA. Teratogenic effects of these CNS-active compounds were evaluated in Naval Medical Research Institute (NMRI) mice susceptible to VPA-induced teratogenicity by comparing them to those of VPA. METHODS: Pregnant NMRI mice were given a single sc injection of either VPA or TMC-amide derivatives on gestation day 8.5, and then the live fetuses were examined to detect any external malformations on gestation day 18. After double-staining for bone and cartilage, their skeletons were examined. RESULTS: In contrast to VPA, which induced NTDs in a high number of fetuses at 2.4-4.8 mmol/kg, TMCD, TMCD-benzenesulfonamide, and TMCD-thiadiazolesulfonamide at 4.8 mmol/kg and MTMCD at 3.6 mmol/kg did not induce a significant number of NTDs. TMCD-thiadiazolesulfonamide exhibited a potential to induce limb defects in fetuses. Skeletal examination also revealed that fetuses exposed to all four of the tetramethylcyclopropanecarboxamide derivatives developed vertebral and rib abnormalities less frequently than those exposed to VPA. Our results established that TMCD, MTMCD, and TMCD-benzenesulfonamide are distinctly less teratogenic than VPA in NMRI mice. CONCLUSIONS: The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates.

Synthesis and anticonvulsant activity of aromatic tetramethylcyclopropanecarboxamide derivatives.

As part of our ongoing research on potential new antiepileptic drugs (AEDs), a series of tetramethylcyclopropanecarboxamide derivatives containing benzene ring were designed, synthesized, and evaluated for anticonvulsant activities in the murine maximal electroshock (MES) and subcutaneous pentylenetetrazole (scMet) seizure tests. The most potent compound emerging from this study was N-(2,2,3,3-tetramethylcyclopropanecarboxamide)-p-phenyl-sulfonamide (21), possessing an ED(50) value of 26mg/kg in the rat-MES test and a remarkable PI (PI=TD(50)/ED(50)) value above 19. The better anticonvulsant potency of compound 21 and its wider safety margin compared to valproic acid (VPA) and zonisamide make it a potential candidate to become a new AED second-generation to VPA.

Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid.

Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.

Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide.

N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (OM-TMCD) is a methoxyamide derivative of a cyclopropyl analogue of valproic acid (VPA). The structural considerations used in the design of OM-TMCD were aimed to enhance OM-TMCD anticonvulsant potency (compared to VPA) and to prevent VPA's two life-threatening side effects, i.e., induction of neural tube defects (NTDs) and hepatotoxicity. Following i.p. administration to rats OM-TMCD demonstrated a broad spectrum of anticonvulsant activity and showed better potency than VPA in the maximal electroshock seizure and subcutaneous pentylenetetrazole tests as well as in the hippocampal kindling model. OM-TMCD was inactive in the mouse 6-Hz test at 100 mg/kg dose. Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA. OM-TMCD was found to be non-mutagenic and non-pro-mutagenic in the Ames test. It showed a beneficial pharmacokinetic profile in rats, having a high oral bioavailability of 75% and satisfactory values of clearance and volume of distribution. These results support further studies to fully characterize the therapeutic potential of OM-TMCD.

Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug.

2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.

Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain.

Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100-250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40-150 mg/kg), MTMCD (N-methyl-TMCD, 20-100 mg/kg), and TMCU (2,2,3,3-tetramethylcyclopropanecarbonylurea, 40-240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED(50) values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED(50)=269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.

Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain.

Antiepileptic drugs (AEDs) are often utilized in the treatment of neuropathic pain. The major AED valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA's corresponding amide: valpromide (VPD), two of VPAs isomers and their corresponding amides; valnoctic acid (VCA), valnoctamide (VCD), diisopropyl acetic acid (DIA), diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD). VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and exhibit better anticonvuslant potency than VPA. In this study, we assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation model of neuropathic pain (SNL, Chung model). VCA and MVPD were inactive. However, VPD (20-100 mg kg(- 1)), VCD (20-100 mg kg(- 1)) and DID (20-90 mg kg(- 1)) produced dose-related reversal of tactile allodynia with ED50 values of 61, 52 and 58 mgkg(- 1), respectively. All the amides were more potent than VPA (ED50=269 mgkg(- 1)). The antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma concentrations of 125, 24, 18 and 7 mg l(- 1), respectively, with a good pharmacokinetic-pharmacodynamic correlation and a minimal lag response. VCD and DID were found to have minimal motor and sedative side effects at analgesic doses, and were equipotent to GBP, currently the leading drug in neuropathic pain treatment. Consequently, VCD and DID have potential to become new drugs for the treatment of neuropathic pain.