Discovery of a novel series of medium-sized cyclic enteropeptidase inhibitors.

Enteropeptidase is located in the duodenum that involved in intestinal protein digestion. We have reported enteropeptidase inhibitors with low systemic exposure. The aim of this study was to discover novel enteropeptidase inhibitors showing more potent in vivo efficacy while retaining low systemic exposure.

Design, synthesis, and structure-activity relationship of TAK-418 and its derivatives as a novel series of LSD1 inhibitors with lowered risk of hematological side effects.

Lysine-specific demethylase 1 (LSD1) is an enzyme that demethylates methylated histone H3 lysine 4 (H3K4). Inhibition of LSD1 enzyme activity could increase H3K4 methylation levels and treat diseases associated with epigenetic dysregulation. However, known LSD1 inhibitors disrupt the interaction between LSD1 and cofactors such as GFI1B, causing the risk of hematological toxicity, including thrombocytopenia.

Design, Synthesis, and Evaluation of [F]T-914 as a Novel Positron-Emission Tomography Tracer for Lysine-Specific Demethylase 1.

Histone methylation is associated with the pathophysiology of neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) catalyzes histone demethylation in a flavin adenine dinucleotide (FAD)-dependent manner. Thus, inhibiting LSD1 enzyme activity could offer a novel way to treat neurodevelopmental disorders.

Cell-based high-throughput screening for the evaluation of reactive metabolite formation potential.

Here, we established a high-throughput in vitro assay system to predict reactive metabolite (RM) formation. First, we performed the glutathione (GSH) consumption assay to monitor GSH levels as an index of RM formation potential using HepaRG cells pretreated with 500 μM D,L-buthionine-(S,R)-sulfoximine (BSO) and then treated with ticlopidine and diclofenac. Both drugs, under GSH-reduced conditions, significantly decreased relative cellular GSH content by 70% and 34%, respectively, compared with that in cells not pretreated with BSO.

Design, Synthesis, and Evaluation of (2-Aminocyclopropyl)phenyl Derivatives as Novel Positron Emission Tomography Imaging Agents for Lysine-Specific Demethylase 1 in the Brain.

Dysregulation of histone H3 lysine 4 (H3K4) methylation is implicated in the pathogenesis of neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) determines the methylation status of H3K4 through flavin adenine dinucleotide (FAD)-mediated histone demethylation. Therefore, LSD1 inhibition in the brain can be a novel therapeutic option for treating these disorders.

Differential effects of selective agonists of neuromedin U1 and U2 receptors in obese and diabetic mice.

Background And Purpose: Neuromedin U (NmU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both responsible for the NmU-mediated anti-obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor-selective agonists.