Novel difluoromethylated 1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6 receptor antagonist with AMDE-improving properties: Design, synthesis, and biological evaluation

Serotonin type 6 receptor (5-HT6R) has been considered as a particularly promising target for treating cognitive deficits due to the positive effects of its antagonists in a wide range of memory impairment paradigms. In this study, we designed, synthesized, and evaluated a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1yl)-1H-indole derivatives as potent 5-HT6R antagonists. Structure-activity relationship study led to the discovery of five compounds (6a, 6m, 6n, 6p and 6q) with potent binding affinity at 5-HT6R. In in vivo pharmacokinetic studies in rats, 6p showed 30-folds higher AUC (267 ng center dot h/mL) and better bioavailability (34.39 %) than those of 6a (9.37 ng center dot h/mL and 5.95 %, respectively) by using difluoromethyl group replacing a methyl group. Besides, 6p showed good brain penetration with C-b/C-p ratio similar to 6. Based on the pharmacological characteristics and favorable pharmacokinetic properties, 6p was further chosen to evaluate cognition-enhancing property in the preliminary in vivo models. It is identified that 6p not only prevented scopolamine-induced learning deficits in the novel object recognition test but also rescued the recognition barrier caused by scopolamine. Finally, the combination of 6p and donepezil produces synergistic effects on increasing the acetylcholine levels in the intracerebral hippocampus. In light of these findings, we propose 6p as a potential 5-HT6R antagonist for treatment of AD.

Automated summary

This study discovered a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1yl)-1H-indole derivatives as potent 5-HT6R antagonists. Compound 6p showed excellent pharmacokinetic properties in rats and demonstrated potential cognitive-enhancing effects in in vivo models. In combination with donepezil, 6p was able to increase acetylcholine levels in the brain, suggesting its potential as a treatment for Alzheimer's disease.