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This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for the decontamination of superficial, nerve agent-contaminated wounds. Anaesthetized animals were randomly assigned to either control (n = 7), no decontamination (n = 12) or WoundStat™ (n = 12) treatment groups. Pigs were exposed to a 5× LD50 dose of neat, radiolabelled S-[2- (diisopropylamino)ethyl]-O-ethyl methyl-phosphonothioate (VX; or equivalent volume of sterile saline for the control group) via an area of superficially damaged skin on the ear. WoundStat™ was applied at 30 seconds post-exposure to assigned animals. The VX contaminant (or saline) and decontaminant remained in place for the duration of the study (up to 6 hours). Physiological parameters and signs of intoxication were recorded during the exposure period. Skin and organ samples were taken post mortem for 14C–VX distribution analyses. Blood samples were taken periodically for toxicokinetic and whole-blood acetylcholinesterase (AChE) activity analyses. VX exposure was accompanied by a rapid decrease in AChE activity in all animals, regardless of decontamination. However, decontamination significantly improved survival rate and time and reduced the severity of signs of intoxication. In addition, the distribution of 14C–VX in key internal organs and post mortem blood samples was significantly lower in the WoundStat™ treatment group. This study demonstrates that WoundStat™ may be a suitable medical countermeasure for increasing both survival rate and time following VX exposure. The results also suggest that AChE activity is not a useful prognostic indicator.

Two difluorinated analogues of FPL 64176 (methyl 4-(2-benzylbenzoyl)-2,5-dimethylpyrrole-3-carboxylate) have been synthesized in three steps from 6-fluorophthalide and methyl 2,5-dimethylpyrrole-3-carboxylate. Significant overlap of signals was observed in the aromatic regions of the 1 H NMR spectra of these compounds. Using 1 H- 1 H and 1 H- 19 F NOE difference spectroscopy it was possible to identify and assign all aromatic resonances and, based on the NOEs observed, differentiate between the positional isomers and definitely assign the structure of each.

Analogs of the L-type calcium channel agonist FPL 64176 (5) were prepared in which the chain length separating the two aryl moieties was varied between zero and four. FPL 64176 (5) and phenethyl derivative 19 were the most potent compounds tested, displaying EC50 values for enhancing calcium influx into GH3 cells of 1−2×10−7 M.

Several 1,2,4-triazole derivatives containing a 2-fluorophenyl substituent at either the 3- or 5-position and a methyl group at the 4-position were synthesized. These derivatives exhibit long-range 19F-1H and 19F-13C through-space coupling in their 1H and 13C nmr spectra between the fluorine and the 4-methyl group. The close spatial proximity of these nuclei was confirmed by X-ray analysis and by fluorine irradiated proton observe ({19F}-1H) NOE difference spectroscopy.

9,9a-Dihydro-2,9a-dimethyl-4-oxo-4H-benz[f]indole-3-carboxylic acid, methyl ester was formed in varying amounts from the Friedel-Crafts-based synthesis of benzoylpyrrole calcium channel activators. The structure of this by-product was determined using two-dimensional long-range 1 H- 13 C heteronuclear correlated and INADEQUATE nmr techniques

9,9a-Dihydro-2,9a-dimethyl-4-oxo-4H-benz[f]indole-3-carboxylic acid, methyl ester was formed in varying amounts from the Friedel-Crafts-based synthesis of benzoylpyrrole calcium channel activators. The structure of this by-product was determined using two-dimensional long-range 1 H- 13 C heteronuclear correlated and INADEQUATE nmr techniques

Friedel-Crafts acylation of methyl 2,5-dimethylpyrrole-3-carboxylate with 2-chloromethylbenzoyl chloride generated the corresponding 4-(2-chloromethylbenzoyl)pyrrole which was reacted in situ with benzene and aluminum chloride to yield the novel calcium channel activator FPL 64176.

Several 1,2,4-triazole derivatives containing a 2-fluorophenyl substituent at either the 3- or 5-position and a methyl group at the 4-position were synthesized. These derivatives exhibit long-range 19F-1H and 19F-13C through-space coupling in their 1H and 13C nmr spectra between the fluorine and the 4-methyl group. The close spatial proximity of these nuclei was confirmed by X-ray analysis and by fluorine irradiated proton observe ({19F}-1H) NOE difference spectroscopy.

Friedel-Crafts acylation of methyl 2,5-dimethylpyrrole-3-carboxylate with 2-chloromethylbenzoyl chloride generated the corresponding 4-(2-chloromethylbenzoyl)pyrrole which was reacted in situ with benzene and aluminum chloride to yield the novel calcium channel activator FPL 64176.

A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.