Modulation of Peripheral Serotonin Levels by Novel Tryptophan Hydroxylase Inhibitors for the Potential Treatment of Functional Gastrointestinal Disorders

• Published in: Journal of medicinal chemistry Vol. 51; no. 13; pp. 3684 - 3687
• Main Authors: Shi, Zhi-Cai, Devasagayaraj, Arokiasamy, Gu, Kunjian, Jin, Haihong, Marinelli, Brett, Samala, Lakshman, Scott, Sheldon, Stouch, Terry, Tunoori, Ashok, Wang, Ying, Zang, Yi, Zhang, Chengmin, Kimball, S. David, Main, Alan J, Sun, Weimei, Yang, Qi, Nouraldeen, Amr, Yu, Xiang-Qing, Buxton, Eric, Patel, Shiv, Nguyen, Nghi, Swaffield, Jon, Powell, David R, Wilson, Alan, Liu, Qingyun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.07.2008; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Cross-Linking Reagents - chemistry; Crystallography, X-Ray; Digestive system; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Gastrointestinal Diseases - drug therapy; Gastrointestinal Diseases - enzymology; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Mice; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Serotonin - metabolism; Structure-Activity Relationship; Tryptophan Hydroxylase - antagonists & inhibitors; Tryptophan Hydroxylase - chemistry; Tryptophan Hydroxylase - metabolism; SYSTEM; TPH1; SPECIFICITY; PHARMACOLOGY; TETRAHYDROBIOPTERIN; AMINO-ACID HYDROXYLASES; BINDING; IRRITABLE-BOWEL-SYNDROME; PARA-CHLOROPHENYLALANINE; Nitrogen heterocycle; Gastrointestinal; Modeling; Aminoester; Structure activity relation; Six membered ring; Molecular model; Inhibition; Chemical synthesis; Peripheral nervous system; Serotonin; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Prodrug; In vitro; In vivo; α-Aminoacid; Vertebrata; Mammalia; Treatment; Mouse; Tryptophan 5-monooxygenase; Biphenyl derivatives; Animal; Pyrimidine derivatives; Digestive diseases; Fluorine Organic compounds; Oxidoreductases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800338j

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.