Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1 H-pyrrol-1-yl)-1 H-pyrazole-3-carboxamides as cannabinoid receptor ligands

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A series of N-alkyl 1-aryl-5-(1 H-pyrrol-1-yl)-1 H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB 1. n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB 1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB 1 receptor affinity (compound 24: K i = 45.6 nM; 29: K i = 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB 1 ligands.