Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors

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• 作者：Daniel R. Goldberg^a ; ^{dgoldberg@kineta.us" class="auth_mail" title="E-mail the corresponding author} ; Sté ; phane De Lombaert^a ; Robert Aiello^a ; Patricia Bourassa^a ; Nicole Barucci^a ; Qing Zhang^a ; Vishwas Paralkar^a ; Adam J. Stein^b ; Jim Valentine^a ; William Zavadoski^a
• 关键词：TPH1 ; Peripheral serotonin ; 5-HT ; Medicinal chemistry ; Acyl guanidine
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：26
• 期：12
• 页码：2855-2860
• 全文大小：5480 K

文摘

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 (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.