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

Abstract

Background 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 M 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. Pharmacokinetics After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250 mg QD to 750 mg QID; the median T1/2 for elimination is ~20 hrs, and repeat administration for 14 days doubles Cmax. Pharmacodynamics In ascending-single-dose and multiple dose (14 day) trials in healthy volunteers, LX-1031 2g-4g/day significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by day 5, and persisting over the 14 day exposure. Clinical safety and efficacy 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. Conclusion 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.

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

“…Serotonin [5-hydroxytryptamine (5-HT)] is involved in controlling GI secretion, motility, and visceral perception (41,63). It is, therefore, not surprising that, in patients with IBS, studies have documented alterations in 5-HT levels (6) and 5-HT signaling (4); serotonin and serotonin receptormodulating drugs are vigorously pursued in IBS, despite poor consensus on the optimal end points for trials and the regulatory agency requirement of rigorous safety standards for serotonergic agents because of potential vascular effects (14,15,24). As a result of the widespread interest in serotonin, genetic alterations in serotonergic mechanisms are the most extensively studied genetic associations with IBS.…”

Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness

“…In contrast to differences in bone phenotypes of Tph1 KO mice, our Tph1 KO mice had reduced body fat with normal LBM, confirming leanness in a recent report. 20 Lexicon has extensive experience examining skeletal phenotypes resulting from disrupting mouse genes 16 and Lexicon's expertise in serotonin actions and metabolism resulted in successful clinical trials examining TPH1 inhibitors for irritable bowel 21,22 and carcinoid syndromes. 23 Medicinal chemistry and preclinical pharmacology data for these TPH inhibitors have been published.…”

Paracrine control of steroidogenesis by serotonin in adrenocortical neoplasms

“…As cortisol hypersecreting adrenal tissues frequently express multiple 5-HT receptor types, the most efficient strategy aimed at counteracting in vivo the serotonergic adrenal tone in a therapeutic perspective would be to decrease adrenal 5-HT synthesis by use of tryptophan hydroxylase inhibitors rather than 5-HT receptor antagonists. Tryptophan hydroxylase inhibitors are already used in clinical trials in patients with carcinoid syndrome in which they have proved to efficiently lower peripheral 5-HT levels and reduce the frequency of symptoms (Camilleri, 2011). Selected patients with primary adrenal hypercortisolism could therefore benefit from administration of these compounds in the short term.…”