Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: Goldberg, Daniel R.; De Lombaert, Stéphane; Aiello, Robert; Bourassa, Patricia; Barucci, Nicole; Zhang, Qing; Paralkar, Vishwas; Stein, Adam J.; Valentine, Jim; Zavadoski, William
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 12(2016)
• Page Start: 2855
• Page End: 2860
• Publication Date: 2016-06-15
• Subjects: TPH1 -- Peripheral serotonin -- 5-HT -- Medicinal chemistry -- Acyl guanidine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.057
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90 Å) X-ray structure crystal structure of one of these inhibitors (compound51 ) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.