Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors. Issue 4 (15th February 2016)

• Record Type: Journal Article
• Authors: Goldberg, Daniel R.; De Lombaert, Stéphane; Aiello, Robert; Bourassa, Patricia; Barucci, Nicole; Zhang, Qing; Paralkar, Vishwas; Valentine, James; Zavadoski, William
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 4(2016)
• Page Start: 1124
• Page End: 1129
• Publication Date: 2016-02-15
• Subjects: TPH1 -- Peripheral serotonin -- 5-HT -- Spirocycle; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.01.064
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.