Modulation of peripheral serotonin levels by novel tryptophan hydroxylase inhibitors for the potential treatment of functional gastrointestinal disorders.
The discovery of a novel class of peripheral tryptophan hydroxylase (TPH) inhibitors is described. This class of TPH inhibitors exhibits excellent potency in in vitro biochemical and cell-based assays, and it selectively reduces serotonin levels in the murine intestine after oral administration without affecting levels in the brain. These TPH1 inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.
Shi
Zhi-Cai
ZC
Lexicon Pharmaceuticals, 350 Carter Road, Princeton, New Jersey 08540, USA. zshi@lexpharma.com
Devasagayaraj
Arokiasamy
A
Gu
Kunjian
K
Jin
Haihong
H
Marinelli
Brett
B
Samala
Lakshman
L
Scott
Sheldon
S
Stouch
Terry
T
Tunoori
Ashok
A
Wang
Ying
Y
Zang
Yi
Y
Zhang
Chengmin
C
Kimball
S David
SD
Main
Alan J
AJ
Sun
Weimei
W
Yang
Qi
Q
Nouraldeen
Amr
A
Yu
Xiang-Qing
XQ
Buxton
Eric
E
Patel
Shiv
S
Nguyen
Nghi
N
Swaffield
Jon
J
Powell
David R
DR
Wilson
Alan
A
Liu
Qingyun
Q
D000818:Animals; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D012701:Serotonin; D014365:Tryptophan Hydroxylase