Evaluation of Difluoromethyl Ketones as Agonists of the γ-Aminobutyric Acid Type B (GABA_B) Receptor

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.

In silico structure‐based design of GABAB receptor agonists using a combination of docking and QSAR

“…A set of 22 GABA B agonists (Figure ) were selected from the literature (Attia, Herdeis, & Bräuner‐Osborne, ,; Han et al., ) considering their agonists activities (EC 50 ) in HEK cells; biological assays are described in the work of Han et al. (). We only used the ( R )‐enantiomeric forms of all the compounds in this study, because this is the active enantiomer of Baclofen.…”

“…The GABA B receptor is functional as a heterodimer composed of two subunits, GABA B1 and GABA B2 , which contain 844 and 941 amino acids, respectively. Each GABA B subunit contains two distinct domains, LB1 and LB2.The GABA B1 subunit contains the GABA‐binding site, being responsible for the ligand recognition, while the GABA B2 is the G‐protein activator (Han et al., ). Although there are non‐ligands that bind directly with GABA B2 , however, its ectodomain directly interacts with the GABA B1 ectodomain to enhance agonist affinity, and is required for receptor activity (Jones et al., ; Milligan, ; Ng et al., ).…”

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers mediated by a reaction between phenols and halothane

“…To date, difluoromethyl or difluoromethylene compounds have been studied extensively as well as monofluorinated and trifluoromethylated arenes or aliphatics. [1][2][3][4] Recent progress in difluoromethylene chemistry has successfully led to the discovery of bioactive compounds such as pantoprazole, a proton pump inhibitor [5], and AFP-07, a prostaglandin I2 receptor-selective agonist [6][7][8], which highlights the importance of the difluoromethylene unit in drug discovery (Figure 1). There have been many reports on the construction of difluoromethylene units, such as deoxygenating and conversion of a carbonyl to a difluoromethylene unit using N,N-diethylaminosulfur trifluoride (DAST) [9][10][11][12][13][14], a Reformatsky reaction of ethyl bromodifluoroacetate [15][16][17][18][19][20][21][22][23], and transformations of tetrafluoroethylene with appropriate metal catalysts [24][25][26][27][28][29][30][31].…”

Ligand‐Controlled Regiodivergent Palladium‐Catalyzed Decarboxylative Allylation Reaction to Access α,α‐Difluoroketones

“…[8,9] In addition, this substructure can enhance bioactivities for alternate therapeutic targets, [10] and can serve as an intermediate for further functionalization (Figure 1). [11] Thus, strategies for accessing α,α-difluoroketones should be useful for the development of biological probes.…”

“…a,a-Difluoroketones are a unique substructure in medicinal chemistry that inhibits serine and aspartyl proteases through interactions with the nucleophilic residue of a protease or a water molecule in the active site of the protease to form stable tetrahedral adducts. [8,9] Furthermore, this substructure can also enhance bioactivities for non-protease targets, [10] and it can serve as an intermediate for further functionalization (Figure 1). [11] Therefore, strategies for accessing a,a-difluoroketones should be useful for the development of biological probes.…”