Journal
TRENDS IN PHARMACOLOGICAL SCIENCES
Volume 39, Issue 6, Pages 560-572Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tips.2018.03.004
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Funding
- German Ministry for Education and Research [16V0276]
- German Ministry for Education and Research (DZHK, German Centre for Cardiovascular Research)
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The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds.
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