Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis.

Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Screening using a thermal shift assay for TPH1 binders yielded Compound (2-(4-methylphenyl)-1,2-benzisothiazol-3(2)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of , with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.