Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake.
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.
Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010 Pula (CA), Italy.
Ilaria
I
Manca
Andrea
A
Mastinu
Francesca
F
Olimpieri
Matteo
M
Falzoi
Monica
M
Sani
Stefania
S
Ruiu
Giovanni
G
Loriga
Alessandro
A
Volonterio
Simone
S
Tambaro
Mirko Emilio Heiner
ME
Bottazzi
Matteo
M
Zanda
Gérard Aimè
GA
Pinna
Paolo
P
Lazzari
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C031280:pyrazole