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 T1/2 for elimination is ∼20 h, and repeat administration for 14 days doubles Cmax. 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.