Synthesis and evaluation of N-(5-methyl-3-oxo-1,2- diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenylureas as cholecystokinin antagonists

Abstract

In the search for new cholecystokinin (CCK) ligands, ureidopyrazolines were identified in combinatorial libraries using 168 chemically diverse amines. The structure-activity relationship optimisation of this pyrazoline template 4a resulted in novel 3-oxo-1,2-diphenyl-2,3-di-hydro-1H-pyrazol-4-yl)-N'-phenylureas 5a-5o. These novel CCK ligands have shown to act as mixed CCK-A/CCK-B ligands in a [125]I-CCK-8 receptor binding assay. The best pyrazoline 5e of this series displayed an IC50 of 20 and 25 nmol/L for the CCK-A, and CCK-B receptor, respectively. In a subsequent in vivo evaluation using various behavior pharmacological assays, an anxiolytic effect of these novel diphenylpyrazolinyl ureas was found in the elevated x-maze with an ED50 of 1.7 mg/kg. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.69 mg/kg was determinated for urea 5e and the antidepressant effect had a magnitude comparable to desimipramine.