Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 6, Pages 2456-2465Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301805e
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Funding
- Purdue University
- Ralph W. and Grace M. Showalter Research Trust
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The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABA(B) agonists that are not structurally analogous to known GABA(B) 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 GABA(B) 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.
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