Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors
详细信息 查看全文
- 作者：Daniel R. Goldberg ; dgoldberg@karospharma.com" class="auth_mail" title="E-mail the corresponding author ; Sté ; phane De Lombaert ; Robert Aiello ; Patricia Bourassa ; Nicole Barucci ; Qing Zhang ; Vishwas Paralkar ; James Valentine ; William Zavadoski
- 关键词：TPH1 ; Peripheral serotonin ; 5-HT ; Spirocycle
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：15 February 2016
- 年：2016
- 卷：26
- 期：4
- 页码：1124-1129
- 全文大小：3479 K
文摘
The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT.