LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin

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Abstract

LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10-8-10-7molL-1 range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750mg q.i.d.; the median T1/2 for elimination is ∼20h, and repeat administration for 14days doubles Cmax. In ascending-single-dose and multiple-dose (14days) trials in healthy volunteers, LX-1031, 2-4gday-1 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.

Original languageEnglish (US)
Pages (from-to)193-200
Number of pages8
JournalNeurogastroenterology and Motility
Volume23
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Tryptophan Hydroxylase
Diarrhea
Serotonin
Hydroxyindoleacetic Acid
Healthy Volunteers
Clinical Trials
Irritable Bowel Syndrome
Carcinoid Tumor
Brain
2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3'-methoxybiphenyl-4-yl)ethoxy)-pyrimidin-4-yl)phenyl)propionic acid
Mood Disorders
Rodentia
Safety

Keywords

  • Carcinoid
  • Irritable bowel

ASJC Scopus subject areas

  • Endocrine and Autonomic Systems
  • Gastroenterology
  • Physiology

Cite this

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title = "LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin",
abstract = "LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10-8-10-7molL-1 range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750mg q.i.d.; the median T1/2 for elimination is ∼20h, and repeat administration for 14days doubles Cmax. In ascending-single-dose and multiple-dose (14days) trials in healthy volunteers, LX-1031, 2-4gday-1 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.",
keywords = "Carcinoid, Irritable bowel",
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AU - Camilleri, Michael

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N2 - LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10-8-10-7molL-1 range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750mg q.i.d.; the median T1/2 for elimination is ∼20h, and repeat administration for 14days doubles Cmax. In ascending-single-dose and multiple-dose (14days) trials in healthy volunteers, LX-1031, 2-4gday-1 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.

AB - LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10-8-10-7molL-1 range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750mg q.i.d.; the median T1/2 for elimination is ∼20h, and repeat administration for 14days doubles Cmax. In ascending-single-dose and multiple-dose (14days) trials in healthy volunteers, LX-1031, 2-4gday-1 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.

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