O

Novel 6-aminopurine compounds, for example, (452) have been claimed by Pfizer as particularly useful in the treatment of obesity and alcohol abuse [302]. In conjunction with an opioid receptor antagonist, the related compounds such as (453) are claimed as a combination therapy for treating alcohol, cocaine or tobacco addiction or dependence, reducing alcohol withdrawal symptoms and aiding in the cessation or lessening of alcohol abuse, substance abuse or behavioural dependency, including gambling [303]. Compound (453) has also been claimed to have utility in combination with a nicotinic acetylcholine agonist in the treatment of obesity or compulsive overeating [304] and compulsive gambling, nicotine and drug dependence [305].

Thiazole-based cannabinoid CB1 modulators were claimed in two patent applications by AstraZeneca [306, 307] where the strategy of bioisosteric pyrazole-replacement is evidenced by the specified compounds (454) and (455), respectively. No specific biological data were presented but the specified compounds were stated to have IC50 values <200 nM. A central thiazole motif was also utilised by Solvay Pharmaceuticals [308]. In vivo antagonism was evaluated using CP 55,940-induced hypotension in rats, however no specific results were given. Compound (455) was shown to have broadly similar affinity at both CB1 and CB2 receptor subtypes with pK values of 7.8 and 8.1, respectively.

A thiazole core has also been utilised by Solvay Pharmaceuticals [309] in the search for a novel bioisosteric replacement of the rimonabant (382) pyrazole core. The affinity of several compounds for the human CB1 receptor was determined in transfected CHO cells using tritium-labelled CP 55940. Antagonism was determined in the same cell line by WIN 55212-2-induced release of arachidonic acid. The pK of (456) was found to be 6.9, while the pA2 value was measured as 8.7. A series of six 1,2,4-triazole analogues has been prepared by Jagerovic et al. [310], via their corresponding N-acylbenzamides (Table 6.39).

Table 6.39 STRUCTURES OF 1,2,4-TRIAZOLE ANALOGUES OF RIMONABANT (382)

Table 6.39 STRUCTURES OF 1,2,4-TRIAZOLE ANALOGUES OF RIMONABANT (382)

Cpd.

0 0

Post a comment