A5031810478- Sleep and Wakefulness Research
- Circadian rhythm and melatonin
- Chemical synthesis and alkaloids
- Cholesterol and Lipid Metabolism
- Receptor Mechanisms and Signaling
- Hormonal Regulation and Hypertension
- Neuroscience and Neuropharmacology Research
- Steroid Chemistry and Biochemistry
- Alzheimer's disease research and treatments
- Synthetic Organic Chemistry Methods
- Marine Sponges and Natural Products
- Drug Transport and Resistance Mechanisms
- Sleep and related disorders
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cholinesterase and Neurodegenerative Diseases
- Epigenetics and DNA Methylation
- Cannabis and Cannabinoid Research
- Synthesis and Characterization of Pyrroles
- Neuroendocrine regulation and behavior
- Synthesis and Biological Evaluation
- Genetics and Neurodevelopmental Disorders
- Genetic Syndromes and Imprinting
- Computational Drug Discovery Methods
- Advanced Synthetic Organic Chemistry
Takeda (Japan)
2014-2024
National Cancer Center Hospital East
2022
Hamamatsu Photonics (Japan)
2003
The University of Tokyo
2000-2001
Kitasato University
2001
Suntory (Japan)
2001
Abstract Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24 S -hydroxycholesterol, the primary mechanism of catabolism in brain. The therapeutic potential CH24H activation has been extensively investigated, whereas effects inhibition remain poorly characterized. In this study, was investigated using newly identified small molecule, soticlestat (TAK-935/OV935). biodistribution and target engagement assessed mice. CH24H-knockout mice showed...
Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain. Because 2-AG AA are endogenous biologically active ligands brain, inhibition of MAGL an attractive therapeutic target for CNS disorders, particularly neurodegenerative diseases. In this study, we report structure-based drug design novel piperazinyl pyrrolidin-2-ones starting from our hit compounds 2a 2b. By enhancing interaction...
Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays role in the homeostasis of brain cholesterol by converting to 24S-hydroxycholesterol (24HC). Despite wide range potential CH24H as drug target, no potent and selective inhibitors have been identified. Here, we report on structure-based design (SBDD) novel 4-arylpyridine derivatives based X-ray co-crystal structure hit derivative 1b. Optimization led us identify 3v...
Abstract The OX 2 orexin receptor (OX R) is a highly expressed G protein-coupled (GPCR) in the brain that regulates wakefulness and circadian rhythms humans. Antagonism of R proven therapeutic strategy for insomnia drugs, agonism potentially powerful approach narcolepsy type 1, which characterized by death orexinergic neurons. Until recently, had been considered ‘undruggable.’ We harness cryo-electron microscopy R-G protein complexes to determine how first clinically tested agonist TAK-925...
Loss of orexin neurons is associated with narcolepsy type 1 (NT1), which characterized by multiple symptoms including excessive daytime sleepiness and cataplexy. Orexin 2 receptor (OX2R) knockout (KO) mice, but not (OX1R) KO show narcolepsy-like phenotypes, thus OX2R agonists are potentially promising for treating NT1. In fact, in early proof-of-concept studies, intravenous infusion danavorexton, an OX2R-selective agonist, significantly increased wakefulness individuals However, danavorexton...
Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation inspiratory neurons in pre-Bötzinger complex, which are critical for generation rhythm, phrenic hypoglossal motoneurons. Herein, we assessed effects OX2R-selective agonists TAK-925 (danavorexton) OX-201 on respiratory function. In vitro electrophysiologic analyses using rat medullary slices, danavorexton showed tendency significant effect, respectively, increasing...
A new excitatory amino acid, neodysiherbaine (2), was isolated as a minor constituent of the aqueous extract from marine sponge Dysidea herbacea. The structure deduced by spectroscopic methods and established unambiguously total synthesis. present synthesis, including key step cross-coupling 6/5-bicyclic core with an acid residue, is useful in constructing its structural analogues.
Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT1/MT2) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening central cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine a potent scaffold with high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of side chains led to identification MT1/MT2 agonist 4d (MT1, Ki = 0.062 nM; MT2, 0.420 nM) good oral absorption...
A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified a potent mimic the 5-methoxy indole core melatonin, introduction cyclohexylmethyl group at 7-position this afforded an ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound full agonist for MT(2) subtype exhibited reentrainment effects to new light/dark cycle in ICR mice 3-30 mg/kg. result demonstrated involvement...
Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase involved in endocannabinoid and inflammatory signaling. Positron-emission tomography (PET) imaging of MAGL serves to validate target engagement therapeutic inhibitors as well investigate levels under normal disease conditions. However, PET radioligands with reversible binding kinetics for MAGL, which allow quantitative assessment are hitherto unavailable. In this study, we designed synthesized fluoro-containing probes starting...
Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain homeostasis. For the development of novel and potent CH24H inhibitor, we designed synthesized 3,4-disubstituted pyridine derivatives using structure-based drug design approach starting from compounds 1 (soticlestat) 2 (thioperamide). Optimization this series by focusing on ligand-lipophilicity efficiency value resulted...
Abstract Purpose Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays major role in brain cholesterol homeostasis by converting into 24 S -hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) being pursued as drug for treatment of seizures developmental and epileptic encephalopathies. Herein, we describe the successful discovery preclinical validation novel radiolabeled ligand (3-[ 18...
Dysregulation of histone H3 lysine 4 (H3K4) methylation is implicated in the pathogenesis neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) determines status H3K4 through flavin adenine dinucleotide (FAD)-mediated demethylation. Therefore, LSD1 inhibition brain can be a novel therapeutic option for treating these Positron emission tomography (PET) imaging allows investigating expression levels under normal and disease conditions validating target engagement inhibitors. This...
O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a and novel OGA inhibitor, compound 5i, comprising aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining...
To develop potent and orally bioavailable melatonin receptor (MT1 MT2) agonists, a novel series of 5–6–5 tricyclic derivatives was designed, synthesized, evaluated. The synthesized indeno[5,4-d][1,3]oxazole, cyclopenta[c]pyrazolo[1,5-a]pyridine, indeno[5,4-d][1,3]thiazole, cyclopenta[e]indazole showed binding affinities for MT1/MT2 receptors. Further optimization these based on their metabolic stability in human hepatic microsomes revealed that (S)-3b...