5J6D

Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors

Summary for 5J6D

• Entry DOI: 10.2210/pdb5j6d/pdb
• Descriptor: Tryptophan 5-hydroxylase 1, FE (III) ION, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (6 entities in total)
• Functional Keywords: tph1, iron, acyl, quanidine, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72542.12

Authors

Stein, A.J.,Goldberg, D.R.,De Lombaert, S. (deposition date: 2016-04-04, release date: 2016-05-25, Last modification date: 2023-09-27)

Primary citation

Goldberg, D.R.,De Lombaert, S.,Aiello, R.,Bourassa, P.,Barucci, N.,Zhang, Q.,Paralkar, V.,Stein, A.J.,Valentine, J.,Zavadoski, W.
Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors.
Bioorg.Med.Chem.Lett., 26:2855-2860, 2016

PubMed 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 (1.90Å) 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.

PubMed: 27146606
DOI: 10.1016/j.bmcl.2016.04.057

Experimental method

X-RAY DIFFRACTION (1.9 Å)