Fivemembered ring pyrazole bioisostere CB1 antagonists

Ring bioisosterism, one of the most frequent relationships in drugs of different therapeutic classes has been widely used to design new cannabinoid antagonists. The first patent application describing analogs of rimonabant in which the central pyrazole ring was replaced by another heterocycle was published in 2003, in the imidazole series [34]. Since then, more than 25 patent applications have been published using this approach.

4,5-Diarylimidazoles were the first reported bioisosteres [34]. The synthesis and SAR of these compounds is discussed in a recent paper that introduced (13) as a potent CB1 antagonist (IC50, hCBl = 6.1 nM). Preliminary pharmacokinetic evaluation in rats indicated good oral absorption (F = 50%) and brain penetration for compound (13), which was also active in a food intake and weight-loss study in diet-obese rats [35].

Related patent applications for the regioisomeric 1,2-diaryl imidazoles were successively filed by three independent groups [36-38]. Some compounds in this series such as (14) displayed affinities for hCBl similar to that of rimonabant and were orally active in mechanistic models [39,40]. Recently, 1,2-diaryl imidazoles such as (15) in which the 5 position is substituted by more polar groups were also reported [41]. A binding activity below 10 nM was found for the latter compound.


The corresponding triazoles have been described by two independent groups which concluded that replacement of a 5-methylimidazole by a triazole led to a loss in CB1 affinity by about ten-fold [39,40,42]. Interestingly, a triazole derivative in which an n-hexyl group replaced the carboxamide group was reported to behave as a CB1 antagonist both in vivo and in functional assays, despite a very moderate affinity for rCB1 receptors [43].

Similarly, 2,3-diaryl oxazoles [35] and thiazoles [39,44,45] were reported to be about one log less potent than the corresponding 5-methyl 1,2-diarylimidazoles. This difference in activity was attributed to the methyl group of the imidazole compounds, which may play a role in favorably orienting the amide nitrogen substituent, as the non-methylated imidazoles, as well as the triazoles, oxazoles and thiazoles lacking the orienting methyl group were all less potent than the 5-methylimidazoles. Similarly, in the 4,5-diaryl imidazoles series, the NMe compounds were found to be much more potent than the corresponding NH compounds [35].

Two patent applications concerning 1,5-diaryl pyrrole-3-carboxamides have also been filed [46,47]. Although one of these does not specifically claim use as CB1 antagonists, but rather for "compounds treating obesity", the compounds described are closely related to SR141716. This publication reports a significant decrease in food consumption following oral administration of compound (16). Conforma-tionally restrained analogs of these molecules were also prepared by bridging the methyl group with the adjacent amide nitrogen, leading to compounds such as (17) [48]. Other patent applications describing pyrroles and imidazoles have also been published by an independent group. In these patents that each include more than 300 examples, the substituent in position 1 includes both aromatic and non-aromatic groups such as methylcyclohexyl, and the substituent in position 5 may be a substituted phenyl or thiazole ring [49,50].

A large number of fused bicyclic derivatives of diaryl-pyrazole and imidazole were reported in a series of eight patent applications. Among these are the purine derivatives (18) and the pyrazolo-triazine (19) [51,52]. Although no specific biological data is available for these compounds, the patent applications claim affinities below 1 nM for some non-specified examples.


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