Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors.
Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. Here we describe the discovery of substituted triazines as a novel class of tryptophan hydroxylase inhibitors. This class of TPH inhibitors can selectively reduce serotonin levels in murine intestine after oral administration without affecting levels in the brain. These TPH inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.
Jin
Haihong
H
Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, USA. hjin@lexpharma.com
Cianchetta
Giovanni
G
Devasagayaraj
Arokiasamy
A
Gu
Kunjian
K
Marinelli
Brett
B
Samala
Lakshman
L
Scott
Sheldon
S
Stouch
Terry
T
Tunoori
Ashok
A
Wang
Ying
Y
Zang
Yi
Y
Zhang
Chengmin
C
David Kimball
S
S
Main
Alan J
AJ
Ding
Zhi-Ming
ZM
Sun
Weimei
W
Yang
Qi
Q
Yu
Xiang-Qing
XQ
Powell
David R
DR
Wilson
Alan
A
Liu
Qingyun
Q
Shi
Zhi-Cai
ZC
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D012701:Serotonin; D014365:Tryptophan Hydroxylase