Document Report Card

ID: ALA2321794

Journal: J Med Chem

Title: Evaluation of difluoromethyl ketones as agonists of the γ-aminobutyric acid type B (GABAB) receptor.

Authors: Han C, Salyer AE, Kim EH, Jiang X, Jarrard RE, Powers MS, Kirchhoff AM, Salvador TK, Chester JA, Hockerman GH, Colby DA.

Abstract: The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABAB agonists that are not structurally analogous to known GABAB agonists, such as baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl ketones were assembled in three synthetic steps using a trifluoroacetate-release aldol reaction. Following evaluation at clinically relevant GABA receptors, we have identified a difluoromethyl ketone that is a potent GABAB agonist, obtained its X-ray structure, and presented preliminary in vivo data in alcohol-preferring mice. The behavioral studies in mice demonstrated that this compound tended to reduce the acoustic startle response, which is consistent with an anxiolytic profile. Structure-activity investigations determined that replacing the fluorines of the difluoromethyl ketone with hydrogens resulted in an inactive analogue. Resolution of the individual enantiomers of the difluoromethyl ketone provided a compound with full biological activity at concentrations less than an order of magnitude greater than the pharmaceutical, baclofen.

CiteXplore: 23428109

DOI: 10.1021/jm301805e