Methoxy- and fluorine-substituted analogs of O-1302: Synthesis and in vitro binding affinity for the CB1 cannabinoid receptor

Abstract

Methoxy and fluorine analogs substituted on the terminal carbon of the pentyl chain of N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4- pentylphenyl)-1H-pyrazole-3-carboxamide (O-1302) were synthesized in a multi-step process from 5-phenyl-1-pentanol, which was based on the 1,5-diarylpyrazole core template of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) through condensation of the respective amine with pyrazole carboxylic acid, in order to develop tracers for medical imaging. Their potency for inhibiting the binding of the CB1 antagonist [3H]SR141716 was evaluated with the aim of developing positron emission tomography (PET) ligands for the cerebral cannabinoid CB1 receptor. These analogs bearing a piperidinyl carboxamide at the C3 of the pyrazole ring exhibited affinities comparable to those of the CB1 reference antagonist SR141716, which warrants further investigation using the radiolabeled form for biological imaging studies. A morpholine ring substituted at the C3 of the pyrazole ring resulted in a reduction of the CB1 affinity. © 2007 Pharmaceutical Society of Japan.