The Synthesis And Biological Evaluation Of Quinolyl-Piperazinyl Piperidines As Potent Serotonin 5-Ht1a Antagonists

As part of an effort to identify 5-HT1A antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT1A antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT1A antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SA R studies, driven primarily by in vitro liver microsomal stability assessment, identified compound lob, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.