Investigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric Approach

Claudia Mugnaini, Stefania Nocerino, Valentina Pedani, Serena Pasquini, Andrea Tafi, Maria De Chiaro, Luca Bellucci, Massimo Valoti, Francesca Guida, Livio Luongo, Stefania Dragoni, Alessia Ligresti, Avraham Rosenberg, Daniele Bolognini, Maria Grazia Cascio, Roger G Pertwee, Ruin Moaddel, Sabatino Maione, Vincenzo Di Marzo, Federico Corelli

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23 Citations (Scopus)

Abstract

Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3-triazole derivative (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compound.
Original languageEnglish
Pages (from-to)920-934
Number of pages15
JournalChemMedChem
Volume7
Issue number5
Early online date2 Mar 2012
DOIs
Publication statusPublished - May 2012

Keywords

  • bioisosteres
  • cannabinoids
  • quinolones
  • receptors
  • structure-activity relationship

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    Mugnaini, C., Nocerino, S., Pedani, V., Pasquini, S., Tafi, A., De Chiaro, M., Bellucci, L., Valoti, M., Guida, F., Luongo, L., Dragoni, S., Ligresti, A., Rosenberg, A., Bolognini, D., Cascio, M. G., Pertwee, R. G., Moaddel, R., Maione, S., Di Marzo, V., & Corelli, F. (2012). Investigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric Approach. ChemMedChem, 7(5), 920-934. https://doi.org/10.1002/cmdc.201100573