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(-7) mol L(-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 250-750 mg q.i.d.; the median T(1/2) for elimination is ∼ 20 h, and repeat administration for 14 days doubles C(max) . In ascending-single-dose and multiple-dose (14 days) trials in healthy volunteers, LX-1031, 2-4 g day(-1) significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14 day 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 (2/4 weeks) 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.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research Center, Mayo Clinic, Rochester, MN 55905, USA. camilleri.michael@mayo.edu
authors.forename: M
authors.initials: M
authors.lastname: Camilleri
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003967:Diarrhea / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D004311:Double-Blind Method; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; 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; D011985:Receptors, Serotonin; D012701:Serotonin; D010649:Phenylalanine; D014365:Tryptophan Hydroxylase