Agonists of the γ-aminobutyric acid type B (GABAB) receptor derived from β-hydroxy and β-amino difluoromethyl ketones.

Munia F Sowaileh, Amy E Salyer, Kuldeep K Roy, Jinu P John, James R Woods, Robert J Doerksen, Gregory H Hockerman, David A Colby

Bioorganic & medicinal chemistry letters 2018 Sep 01

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β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series. Copyright © 2018 Elsevier Ltd. All rights reserved.

Citation

Munia F Sowaileh, Amy E Salyer, Kuldeep K Roy, Jinu P John, James R Woods, Robert J Doerksen, Gregory H Hockerman, David A Colby. Agonists of the γ-aminobutyric acid type B (GABAB) receptor derived from β-hydroxy and β-amino difluoromethyl ketones. Bioorganic & medicinal chemistry letters. 2018 Sep 01;28(16):2697-2700