The development of new synthetic methodologies for the preparation of fluorine-containing molecules is an area of intense investigation in the pharmaceutical industry. Difluoromethyl ketones are prominent examples of such fluorinated compounds, because the ketone reverts to a hydrate in the presence of water which may impart promising new biological activity. Recently, we have discovered that trifluoroacetate release is a powerful synthetic process for executing aldol reactions with difluoroenolates and for assembling difluoromethyl ketones. Pharmacological evaluation of these scaffolds has lead to the identification of selective agonists of the GABA-B receptor. These unique molecules are not based on the structure of GABA and this feature distinguishes them from nearly all of the other known selective GABA-B agonists. This presentation will describe the synthesis, discovery, and pharmacological evaluation of novel difluoromethyl ketones as agonist of the GABA-B receptor. Preliminary behavioral studies in mice for the lead compound will be disclosed.

Synthesis, pharmacological evaluation, and behavioral studies in mice of difluoromethyl ketones as novel and selective agonists of the GABA-B receptor

245th National Meeting (2013)

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