Novel pyrazole derivatives as neutral CB1 antagonists with significant activity towards food intake

Ilaria Manca, Andrea Mastinu, Francesca Olimpieri, Matteo Falzoi, Monica Sani, Stefania Ruiu, Giovanni Loriga, Alessandro Volonterio, Simone Tambaro, Mirko Emilio Heiner Bottazzi, Matteo Zanda, Gerard Aime Pinna, Paolo Lazzari

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23 Citations (Scopus)

Abstract

In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.
Original languageEnglish
Pages (from-to)256-269
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume62
Early online date11 Jan 2013
DOIs
Publication statusPublished - Apr 2013

Keywords

  • cannabinoids
  • CB1 receptor
  • fluorinated ligands
  • food intake

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    Manca, I., Mastinu, A., Olimpieri, F., Falzoi, M., Sani, M., Ruiu, S., Loriga, G., Volonterio, A., Tambaro, S., Bottazzi, M. E. H., Zanda, M., Pinna, G. A., & Lazzari, P. (2013). Novel pyrazole derivatives as neutral CB1 antagonists with significant activity towards food intake. European Journal of Medicinal Chemistry, 62, 256-269. https://doi.org/10.1016/j.ejmech.2012.12.056