Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain
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- 作者：Matthew C. Lucas ; Robert J. Weikert ; David S. Carter ; Hai-Ying Cai ; Robert Greenhouse ; Pravin S. Iyer ; Clara J. Lin ; Eun Kyung Lee ; Ann Marie Madera ; Amy Moore ; Kerem Ozboya ; Ryan C. Schoenfeld ; S ; ra
- 关键词：Monoamine reuptake inhibitors ; Triple reuptake inhibitor ; Serotonin ; Norepinephrine ; Noradrenalin ; Dopamine ; Major depressive disorder ; Depression
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2010
- 出版时间：15 September 2010
- 年：2010
- 卷：20
- 期：18
- 页码：5559-5566
- 全文大小：2641 K
文摘
Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug–drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.