5j6d

Publication Abstract from PubMed

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 (1.90A) 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.

Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors.,Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Stein AJ, Valentine J, Zavadoski W Bioorg Med Chem Lett. 2016 Jun 15;26(12):2855-60. doi:, 10.1016/j.bmcl.2016.04.057. Epub 2016 Apr 21. PMID:27146606^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.