Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. Serotonin plays important physiological roles both peripherally and centrally. LX-1031 is a heterocyclic substituted phenylalanine analog, an oral small molecule tryptophan hydroxylase (TPH) inhibitor that reduces synthesis of serotonin (5-HT) peripherally and is being developed for conditions characterized by excess 5-HT expression such as diarrhea-predominant irritable bowel syndrome (IBS-D) and, possibly, carcinoid diarrhea.
In vitro: LX-1031 inhibits TPH1 at its concentration of 10-8–10-7 mol L-1 range [1].
In vivo: With oral administration of LX-1031 in mice, the 5-HT reductions in the jejunum relative to control were ~33%, 51%, and 66% with the 15, 45 and 135 mg/kg/day doses, respectively; the effect of 5 mg/kg/day on GI 5-HT content was not significantly different from control [2].
Clinical trial: In double-blind studies (doses of LX-1031 ranging from 250 to 1000 mg q.i.d.), average 5HIAA reductions of 33% were noted. In phase I studies, 54 healthy volunteers received the drug for up to 14 days while the diet was strictly controlled to avoid 5-HT-rich foods. Twenty four hour urine collections were obtained. Significant reductions in urinary 5-HIAA persisted over the duration of exposure [3].
References:
[1] Camilleri M. LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin. Neurogastroenterol Motil. 2011;23(3):193-200.
[2] Brown PM, Jackson JI, Frazier KS, Turner CA, Shi ZC, Liu Q. From mouse knockout to investigational drug: LX1031, a novel potential treatment for irritable bowel syndrome. Am J Gastroenterol 2007; 102: S961 (Abstract).
[3] Freiman J, Jackson J, Frazier KS, Yang QM, Liu Q, Brown P. LX1031: inhibition of 5-HT synthesis as a new target in the management of irritable bowel syndrome (IBS). Neurogastroenterol Motil 2009; 21: 250.