title: LX-1031, a tryptophan 5-hydroxylase inhibitor that reduces 5-HT levels for the potential treatment of irritable bowel syndrome.
abstract: LX-1031, being developed by Lexicon Pharmaceuticals, is an oral, small-molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces 5-HT synthesis peripherally. LX-1031 is being developed for the potential treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), which is characterized by excess 5-HT. In preclinical studies, LX-1031 dose-dependently reduced expression of 5-HT in the duodenum, jejunum and ileum, but had no effect on brain 5-HT levels. In ascending single-dose and multiple-dose (14 day) phase I clinical trials in healthy volunteers, LX-1031 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA; a marker of 5-HT metabolism) levels, starting by day 5 and persisting over the duration of exposure. In a phase II clinical trial in patients with IBS-D, a 1000-mg qid dose of LX-1031 was associated with improved weekly global scores and stool consistency, and lower urinary 5-HIAA levels over a 28-day treatment period. LX-1031 was well tolerated in trials to date. In conclusion, LX-1031 appears promising for IBS-D. Optimal doses, efficacy in IBS clinical trials and safety need to be fully elucidated.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Charlton 8-110, 200 First St SW, Rochester, MN 55905, USA. camilleri.michael@mayo.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D015507:Drugs, Investigational / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D010649:Phenylalanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: C557875:2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3'-methoxybiphenyl-4-yl)ethoxy)-pyrimidin-4-yl)phenyl)propionic acid; D001713:Biphenyl Compounds; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D012702:Serotonin Antagonists; D010649:Phenylalanine; D014365:Tryptophan Hydroxylase