The Synthesis and Biological Evaluation of Quinolyl-piperazinyl Piperidines as Potent Serotonin 5-HT1A Antagonists
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- 作者：Wayne E. Childers ; Jr. ; Lisa M. Havran ; Magda Asselin ; James J. Bicksler ; Dan C. Chong ; George T. Grosu ; Zhongqi Shen ; Magid ; A. Abou-Gharbia ; Alvin C. Bach ; III ; Boyd L. Harrison ; Natasha Kagan ; Tere
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：May 27, 2010
- 年：2010
- 卷：53
- 期：10
- 页码：4066-4084
- 全文大小：1294K
- 年卷期：v.53,no.10(May 27, 2010)
- ISSN：1520-4804
文摘
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. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, 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.