Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists

As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophe nyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compoun d for initiating studies designed to examine the structure-activity relatio nships of related compounds and to search for more selective and potent can nabimimetic ligands. A series of pyrazole derivatives was designed and synt hesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Thera peutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activi ty included (a) a para-substituted phenyl ring at the 5-position, (b) a car boxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this se ries contained a p-iodophenyl group at the 5-position, a piperidinyl carbox amide at the S-position, and a 2,4-dichlorophenyl group at the 1-position o f the pyrazole ring. The iodinated nature of this compound offers additiona l utility as a gamma-enriching SPECT (single photon emission computed tomog raphy) ligand that may be useful in characterizing brain CB1 receptor bindi ng in vivo.