Biomedical subjects

James Stables

Publications and source records attributed to James Stables.

8 recordsLinked to original sources

PubMed2007

Fluorofelbamate.

The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clinical studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was observed after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (MedPointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metabolism that has demonstrated, in vitro, to avoid the production of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.

Animals↗

PubMed2006

Synthesis and anticonvulsant activity of sulfonamide derivatives-hydrophobic domain.

A series of sulphonamide derivatives (1-11) were synthesized in good yield and evaluated for their possible anticonvulsant activity and neurotoxic study. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Majority of the compounds were active in MES and scPTZ tests. All the compounds were less toxic than the standard drug phenytoin.

Animals↗

PubMed2006

Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore.

Two series of pharmacophoric hybrids of phthalimide-GABA-anilides/hydrazones were designed and synthesized and evaluated for their anticonvulsant and neurotoxic properties. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests. All of the compounds were ineffective in the MES test. Most of the compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model.

Anilides↗

PubMed2006

2,4-Dimethoxyphenylsemicarbazones with anticonvulsant activity against three animal models of seizures: synthesis and pharmacological evaluation.

Various 2,4-dimethoxyphenylsemicarbazones were synthesized starting from 2,4-dimethoxyaniline via a phenylcarbamate intermediate. The structures were confirmed by spectral and elemental analyses. The anticonvulsant activity of the synthesized compounds was established after intraperitoneal administration in three seizure models in mice which include maximal electroshock seizure, subcutaneous pentylenetetrazole, and subcutaneous strychnine-induced seizure screens. Nine compounds exhibited protection in all the three seizure models, and N1-(2,4-dimethoxyphenyl)-N4-(propan-2-one)semicarbazone (17) emerged as the most active compound with no neurotoxicity. These compounds were found to elevate gamma-aminobutyric acid (GABA) levels in the midbrain and medulla oblongata regions equipotent to clobazam.

Animals↗

PubMed2005

Discovery of N-(2,6-dimethylphenyl)-substituted semicarbazones as anticonvulsants: hybrid pharmacophore-based design.

Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118% and inhibited the GABA transaminase enzyme both in vitro and ex vivo.

4-Aminobutyrate Transaminase↗

PubMed2005

Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by postmitochondrial suspensions.

Evidence has been presented suggesting that a reactive metabolite, 2-phenylpropenal (ATPAL), may be responsible for the toxicities observed during therapy with the antiepileptic drug felbamate (FBM). Formation of ATPAL from its unstable immediate precursor, 3-carbamoyl-2-phenylpropionaldedhyde (CBMA) requires the loss of the hydrogen atom at position 2 in the propane chain, and it has been postulated that substitution of this atom with fluorine would prevent the formation of ATPAL. On the basis of this hypothesis, 2-fluoro-2-phenyl-1,3-propanediol dicarbamate (F-FBM) was synthesized and is presently undergoing drug development. To test this hypothesis, we compared the metabolism by human liver postmitochondrial suspensions (S9) in vitro of selected FBM and postulated F-FBM metabolites leading to formation of CBMA or 3-carbamoyl-2-fluoro-2-phenyl-propionaldehyde (F-CBMA). All S9 incubations included GSH as a trapping agent for any reactive metabolites formed. Our results indicated that, in phosphate buffer, pH 7.4, at 37 degrees C, the half-life for 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) was 2.8 and 3.6 h in the presence or absence of GSH, respectively; compared to 4-hydroxy-5-fluoro-5-phenyl-tetrahydro-1,3-oxazin-2-one (F-CCMF) which lost only 2.5% or 4.9% over 24 h under the same conditions. When incubated with S9 in the presence of the cofactor, NAD+, 2-phenyl-1,3-propanediol monocarbamate (MCF) was oxidized to CCMF which was further oxidized to 3-carbamoyl-2-phenylpropionic acid (CPPA). 2-Fluoro-2-phenyl-1,3-propanediol monocarbamate (F-MCF) under similar conditions was stable, and no metabolites were observed. When CCMF was incubated with S9 in the presence of NAD+ cofactor, oxidation to CPPA and reduction to MCF were observed. In addition, a new atropic acid GSH adduct (ATPA-GSH) was identified by mass spectrometry. When F-CCMF was incubated under the same conditions as CCMF, both reduced and oxidized metabolites, F-MCF and 3-carbamoyl-2-fluoro-2-phenylpropionic acid (F-CPPA), respectively, were formed but at significantly lower rates, and no GSH conjugates were identified. Our results support the hypothesis that F-FBM and F-CCMF are not metabolized by S9 in vitro to the known reactive FBM metabolite, ATPAL.

Aldehydes↗

PubMed2004

3-Chloro-2-methylphenyl-substituted semicarbazones: synthesis and anticonvulsant activity.

A series of 3-chloro-2-methylphenyl substituted semicarbazones (3-33) was synthesized and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice or rats, the semicarbazone derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), and subcutaneous strychnine (scSTY)-induced seizure and neurotoxicity screens. The aryl urea (1) and the semicarbazide (2) showed anticonvulsant activity in the MES and scPTZ screens with acute neurotoxicity, whereas the semicarbazone derivatives showed good anticonvulsant potency in the scSTY screen with moderate activity against MES and scPTZ screens. Compound 21 exhibited anticonvulsant potency against all the three screens with lesser neurotoxicity. Some titled compounds exhibited lesser CNS depression and neurotoxicity compared to phenytoin or carbamazepine as was evident from the CNS studies.

Animals↗

PubMedDate not supplied

Synthesis and biological activities of diflunisal hydrazide-hydrazones.

Several diflunisal hydrazide-hydrazone derivatives namely 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid [(5-nitro-2-furyl/substitutedphenyl)methylene] hydrazide (3a-o) have been synthesised. Methyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (1) and 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrazide (2) were also synthesised and used as intermediate compounds. All synthesised compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37 Rv, antimicrobial activities against various bacteria, fungi and yeast species. Compound 3a have shown activity against Staphylococcus epidermis HE-5 and Staphylococcus aureus HE-9 at 18.75 and 37.5 microg mL(-1), respectively. Compound 3o have exhibited activity against Acinetobacter calcoaceticus IO-16 at a concentration of 37.5 microg mL(-1), whereas Cefepime, the drug used as standard, have been found less active against the microorganisms mentioned above. The synthesised compounds were found to provide 12-34% inhibition of mycobacterial growth of M. tuberculosis H37 Rv in the primary screen at 6.25 microg mL(-1). Anticonvulsant activity of the compounds were also determined by maximal electroshock (MES) and subcutaneous metrazole (scMET) tests in mice and rats following the procedures of antiepileptic drug development (ADD) program of the National Institutes of Health (NIH). Compound 3k showed 25% protection against MES induced seizures in p.o. rat screening at a dose level of 30 mg kg(-1) whereas 3n and 3o showed neurotoxicity after 4 and 0.5 h at a dose level of 100 and 300 mg kg(-1), respectively.

Animals↗