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.
Lexicon Pharmaceuticals, 350 Carter Road, Princeton, New Jersey 08540, USA. zshi@lexpharma.com
Zhi-Cai
ZC
Shi
Arokiasamy
A
Devasagayaraj
Kunjian
K
Gu
Haihong
H
Jin
Brett
B
Marinelli
Lakshman
L
Samala
Sheldon
S
Scott
Terry
T
Stouch
Ashok
A
Tunoori
Ying
Y
Wang
Yi
Y
Zang
Chengmin
C
Zhang
S David
SD
Kimball
Alan J
AJ
Main
Weimei
W
Sun
Qi
Q
Yang
Amr
A
Nouraldeen
Xiang-Qing
XQ
Yu
Eric
E
Buxton
Shiv
S
Patel
Nghi
N
Nguyen
Jon
J
Swaffield
David R
DR
Powell
Alan
A
Wilson
Qingyun
Q
Liu
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