Cannabinoid Receptor Antagonist - Drug Design - Other Derivatives

Other Derivatives

Structurally different from the 1,5-diarylpyrazoles are the chemical series of the 3,4-diarylpyrazolines. Within this series is SLV-319 (ibipinabant), a potent CB₁ antagonist which is about 1000-fold more selective for CB₁ compared with CB₂ and displays in vivo activity similar to rimonabant.

Another approach used to develop analogs of rimonabant was to replace central pyrazole ring by another heterocycle. An example of this approach are 4,5-diarylimidazoles and 1,5-diarylpyrrole-3-carboxamides.

A large number of fused bicyclic derivatives of diaryl-pyrazole and imidazoles have been reported. An example of these is a purine derivative where a pyrimidine ring is fused to an imidazole ring. Otenabant (CP-945,598) is an example of a fused bicyclic derivative developed by Pfizer.

Several research groups have studied six-membered ring pyrazole bioisosteres. For example one 2,3-diarylpyridine derivative was shown to be potent and selective CB₁ inverse agonist. The structure of this compound demonstrates the possibility that the amide moiety of rimonabant could be split into a lipophilic (benzyloxy) and a polar (nitrile) functionality. Other six-membered ring analogs are for example pyrimidines and pyrazines.

In addition to the five and six-membered ring analogs there are other cyclic derivatives such as the azetidines. One example is the methylsulfonamide azetidine derivative which has a 1,1-diaryl group that mimics the 1,5-diaryl moiety of the diarylpyrazoles. The sulfonyl group serves as a hydrogen bond acceptor. The 1,1-diaryl group is also present in derivatives such as the benzodioxoles and hydantoins.

Acyclic analogs have also been reported. These analogs contain a 1,2-diaryl motif which corresponds to the 1,5-diaryl substituents of rimonabant. An example of an acyclic analog is taranabant (MK-0364) developed by Merck.

Representatives of these analogs are summarized in Table 2.