title: Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors.
abstract: 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.
authors.affiliation: Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, USA. hjin@lexpharma.com
authors.forename: Haihong
authors.initials: H
authors.lastname: Jin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cianchetta
authors.forename: Arokiasamy
authors.initials: A
authors.lastname: Devasagayaraj
authors.forename: Kunjian
authors.initials: K
authors.lastname: Gu
authors.forename: Brett
authors.initials: B
authors.lastname: Marinelli
authors.forename: Lakshman
authors.initials: L
authors.lastname: Samala
authors.forename: Sheldon
authors.initials: S
authors.lastname: Scott
authors.forename: Terry
authors.initials: T
authors.lastname: Stouch
authors.forename: Ashok
authors.initials: A
authors.lastname: Tunoori
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zang
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: David Kimball
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Main
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Ding
authors.forename: Weimei
authors.initials: W
authors.lastname: Sun
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiang-Qing
authors.initials: XQ
authors.lastname: Yu
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Alan
authors.initials: A
authors.lastname: Wilson
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Liu
authors.forename: Zhi-Cai
authors.initials: ZC
authors.lastname: Shi
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D012701:Serotonin; D014365:Tryptophan Hydroxylase