Synthesis and structure-activity relationships (SARs) of 1,5-diarylpyrazole cannabinoid type-1 (CB1) receptor ligands for potential use in molecular imaging

Article abstract of DOI:10.1016/j.bmc.2006.01.047

Cannabinoid type-1 (CB₁) receptor ligands, derived from the 1,5-diarylpyrazole core template of rimonabant (Acomplia), have been the focus of several studies aimed at examining structure-activity relationships (SARs). The purpose of this study was to design and synthesize a set of compounds based on the 1,5-diarylpyrazole template while focusing on the potential for discovery of CB₁ receptor radioligands that might be used as probes with in vivo molecular imaging. Each synthesized ligand was evaluated for potency as an antagonist at CB₁ and cannabinoid type-2 (CB₂) receptors in vitro using a GTPγ³⁵S-binding assay. c log P values were calculated with Pallas 3.0. The antagonist binding affinities (K_B) at CB₁ receptors ranged from 11 to >16,000 nM, CB₁ versus CB₂ selectivities from 0.6 to 773, and c log Ps from 3.61 to 6.25. An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxamide (9j), emerged from the synthesized set with appealing properties (K_B = 11 nM; CB₁ selectivity > 773; c log P = 5.85), for labeling with carbon-11 and development as a radioligand for imaging brain CB₁ receptors in vivo with positron emission tomography (PET).