Cannabinoid Receptor Antagonist - Drug Design - Diarylpyrazole Derivatives

Diarylpyrazole Derivatives

SR141716 (rimonabant) analogs have recently been described by several groups, leading to a good understanding of the structure-activity relationship (SAR) within this chemical group. While most compounds described are less potent than SR141716, two of them are worth mentioning, SR147778 and AM251.

SR147778 (surinabant), a second generation antagonist, has a longer duration of action than rimonabant and enhanced oral activity. This enhanced duration of action is probably due to the presence of the more metabolically stable ethyl group at the 4-position of its pyrazole ring. Another change is the replacement of the 5-phenyl chlorine substituent by bromine.

The diarylpyrazole derivative, AM251, has been described where chlorine substituent has been replaced by iodine in the para position of the 5-phenyl ring. This derivative appeared to be more potent and selective than rimonabant.

21 analogs possessing either an alkyl amide or an alkyl hydrazide of variant lengths in position 3 were synthesized. It was observed that affinity increases with increased carbon chain length up to five carbons. Also the amide analogs exhibited higher affinity than hydrazide analogs. However, none of these analogs possessed significantly greater affinity than rimonabant but nevertheless, they were slightly more selective than rimonabant for the CB₁ receptor over the CB₂ receptor.

Several attempts have been made to increase the affinity of the diarylpyrazole derivatives by rigidifying the structure of rimonabant. In terms of the general pharmacophore model the units A, B and/or C are connected by additional bonds leading to rigid molecules. For example the condensed polycyclic pyrazole NESS-0327 showed 5000 times more affinity for the CB₁ receptor than rimonabant. However, this compound possesses a poor central bioavailability.

Another compound, the indazole derivative O-1248, can be regarded as an analog of rimonabant wherein its 5-aryl group is fused to the pyrazole moiety. However, this structural modification resulted in a 67-fold decrease in CB₁ receptor affinity.

These diarylpyrazole derivatives of rimonabant are summarized in Table 1.