Abstracts

Fluorofelbamate (FFBM) is an analog of felbamate (FBM) that was designed to have similar clinical efficacy of felbamate without its serious adverse effects of aplastic anemia and liver failure. Fluorofelbamate differs from felbamate by substituting fluorine for hydrogen in the 2-position of the propane side chain of felbamate. This specific substitution is thought to prevent the production of a proposed reactive aldehyde metabolite, atropaldehyde (ATPAL), which is produced via beta-elimination from 3-carbamoyl-2-phenylprionaldeyde (CBMA) and is thought to be responsible for the severe idiosyncratic reactions. It has been reported by Thompson et al. (Chem Res Toxicol, 1996) that CBMA is in dynamic equilibrium with 4-hydroxy-5-phenyl-tetrahydro-1,3-oxazin-2-one (CCMF) and that CBMA incubated in the presence of glutathione (GSH) was completely converted to the GSH adduct of ATPAL over 15 hours. Recent work expanded this observation to CCMF and analogous studies were initiated using the fluorinated analog, F-CCMF. Fluorofelbamate is currently in preclinical development and results of pharmacodynamic, pharmacologic, toxicologic and metabolic studies will be presented. The pharmacodynamic and mechanistic profile of FFBM was established using standardized in-vivo anticonvulsant tests. Non-clinical studies in support of an IND submission were conducted at a qualified GLP laboratory. Recently studies in vitro were conducted to compare the metabolism of MCF, FMCF, CCMF, and FCCMF in the presence of glutathione to trap reactive metabolites formed by pooled human liver S9 fractions. Analyses of samples from these studies were performed using HPLC and HPLC/APCI/MS. FFBM demonstrated efficacy in a broad range of animal seizure models. Drug metabolism studies showed that both CCMF and FCCMF were oxidized by human liver S9 fractions to produce 3-carbamoyl-2-phenylpropionic acid (CPPA) and FCPPA. In contrast, in the presence of glutathione, adducts with ATPAL or 2-phenylpropionic acid (ATPALA), respectively, were identified following incubation with CCMF but not FCCMF. We also demonstrated that MCF is metabolized to CCMF and CPPA by human liver S9 fraction. However, FMCF did not produce FCCMF , FCPPA, CCMF or CPPA providing important additional evidence that FFBM does not produce the putative toxic metabolite ATPAL. The results of these studies support the concept that FFBM[apos]s anticonvulsant profile is similar to that for FBM. The non-clinical pharmacology-toxicology work has not identified any major issues and the adduct work demonstrates that reactive intermediates are not formed from FCCMF under the conditions tested. Lastly, results from the human liver S9 metabolic studies in vitro provide evidence that fluorofelbamate will not enter the pathway that generates the putative toxic metabolite, ATPAL, that is generated from felbamate.