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Dive into the research topics where Yoshihisa Nakada is active.

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Featured researches published by Yoshihisa Nakada.


European Journal of Pharmacology | 2010

Coenzyme A: diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets.

Toshihiro Yamamoto; Hiroshi Yamaguchi; Hiroshi Miki; Mitsuyuki Shimada; Yoshihisa Nakada; Masaki Ogino; Kouhei Asano; Kazuko Aoki; Norikazu Tamura; Minori Masago; Koki Kato

Coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of the 2 known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis; this enzyme is considered to be a potential therapeutic target in metabolic disorders such as obesity and its related lipid abnormalities. Compound-Z, a novel specific small-molecule DGAT1 inhibitor, significantly reduced adipose tissue weight and tended to hepatic lipid accumulation in genetically obese KKAy mice. These actions were shown to almost the same extent in both a high-fat feeding condition in which triacylglycerols are synthesized mainly via exogenous fatty acid and a low-fat, high-carbohydrate feeding condition in which triacylglycerols are synthesized mainly via de novo fatty acid synthesis. This inhibitor also significantly reduced plasma and/or hepatic cholesterol levels in KKAy mice in a high-fat feeding condition. This cholesterol-lowering effect was suggested to be due to mainly decreases in cholesterol absorption from the small intestine. These results suggest that Compound-Z is a promising and attractive agent not only for the treatment of obesity but also hepatic steatosis and circulating lipid abnormalities that are the leading causes of atherosclerosis.


Bioorganic & Medicinal Chemistry | 2010

Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives.

Yoshihisa Nakada; Thomas Daniel Aicher; Yvan Le Huerou; Timothy M. Turner; Scott Alan Pratt; Stephen S. Gonzales; Steve A. Boyd; Hiroshi Miki; Toshihiro Yamamoto; Hiroshi Yamaguchi; Koki Kato; Shuji Kitamura

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.


European Journal of Pharmacology | 2011

A novel coenzyme A:diacylglycerol acyltransferase 1 inhibitor stimulates lipid metabolism in muscle and lowers weight in animal models of obesity.

Toshihiro Yamamoto; Hiroshi Yamaguchi; Hiroshi Miki; Shuji Kitamura; Yoshihisa Nakada; Thomas Daniel Aicher; Scott Alan Pratt; Koki Kato

Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis. In this report, we describe the pharmacological effects of a novel selective DGAT1 inhibitor, Compound-A. This compound inhibited triacylglycerol synthesis in both adipocytes and skeletal myotubes, and increased fatty acid oxidation in skeletal myotubes at 1 μM. The repeated administration of Compound-A to diet-induced obese C57BL/6J and genetically obese KKA(y) mice (3-30 mg/kg for 3-4 weeks) significantly decreased the visceral fat pad weights and the hepatic lipid contents compared to controls without affecting food intake. In addition, fatty acid oxidation in skeletal muscle tissues was increased by the treatment of Compound-A in both mice strains. This is the first report demonstrating that a small synthetic DGAT1 inhibitor increases fatty acid oxidation in skeletal muscle in vitro and ex vivo. These results suggest that DGAT1 inhibition is a promising therapeutic approach for the treatment of obesity and lipid abnormalities such as hepatic steatosis.


Bioorganic & Medicinal Chemistry | 2016

Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1 H )-ones as potent and selective PKC θ inhibitors

Taisuke Katoh; Takafumi Takai; Takafumi Yukawa; Tetsuya Tsukamoto; Etsurou Watanabe; Hideyuki Mototani; Takeo Arita; Hiroki Hayashi; Hideyuki Nakagawa; Michael G. Klein; Hua Zou; Bi-Ching Sang; Gyorgy Snell; Yoshihisa Nakada

A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse.


Bioorganic & Medicinal Chemistry | 2017

Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design

Takeshi Yasui; Takeshi Yamamoto; Nozomu Sakai; Kouhei Asano; Takafumi Takai; Yayoi Yoshitomi; Melinda Davis; Terufumi Takagi; Kotaro Sakamoto; Satoshi Sogabe; Yusuke Kamada; Weston Lane; Gyorgy Snell; Masashi Iwata; Masayuki Goto; Hiroshi Inooka; Junichi Sakamoto; Yoshihisa Nakada; Yasuhiro Imaeda

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.


Bioorganic & Medicinal Chemistry | 2016

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Ikuo Fujimori; Tomoya Yukawa; Taku Kamei; Yoshihisa Nakada; Nobuki Sakauchi; Masami Yamada; Yusuke Ohba; Maiko Takiguchi; Masako Kuno; Izumi Kamo; Hideyuki Nakagawa; Teruki Hamada; Tomoko Igari; Teruaki Okuda; Satoshi Yamamoto; Tetsuya Tsukamoto; Yuji Ishichi; Hiroyuki Ueno

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.


Journal of Medicinal Chemistry | 2018

Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors; Analysis of Structure–Kinetic Relationships

Masato Yoshikawa; Morihisa Saitoh; Taisuke Katoh; Tomohiro Seki; Simone V. Bigi; Yuji Shimizu; Tsuyoshi Ishii; Takuro Okai; Masako Kuno; Harumi Hattori; Etsuro Watanabe; Kumar Singh Saikatendu; Hua Zou; Masanori Nakakariya; Takayuki Tatamiya; Yoshihisa Nakada; Takatoshi Yogo

We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.


Bioorganic & Medicinal Chemistry Letters | 2017

Practical application of 3-substituted-2,6-difluoropyridines in drug discovery: Facile synthesis of novel protein kinase C theta inhibitors

Taisuke Katoh; Yoshihide Tomata; Masaki Setoh; Satoshi Sasaki; Takafumi Takai; Yayoi Yoshitomi; Tomoya Yukawa; Hideyuki Nakagawa; Shoji Fukumoto; Tetsuya Tsukamoto; Yoshihisa Nakada

We previously reported a facile preparation method of 3-substituted-2,6-difluoropyridines, which were easily converted to 2,3,6-trisubstituted pyridines by nucleophilic aromatic substitution with good regioselectivity and yield. In this study, we demonstrate the synthetic utility of 3-substituted-2,6-difluoropyridines in drug discovery via their application in the synthesis of various 2,3,6-trisubstituted pyridines, including macrocyclic derivatives, as novel protein kinase C theta inhibitors in a moderate to good yield. This synthetic approach is useful for the preparation of 2,3,6-trisubstituted pyridines, which are a popular scaffold for drug candidates and biologically attractive compounds.


Archive | 2006

HETEROCYCLIC AMIDE COMPOUND AND USE THEREOF

Shotaro Miura; Mitsuyuki Shimada; Shogo Marui; Norikazu Tamura; Yoshihisa Nakada; Ryuichi Tozawa; Junichi Sakamoto; Yasunori Funabashi; Hiroshi Hosono


Archive | 2009

Heterocyclic derivative and use thereof

Nobuyuki Matsunaga; Yoshihisa Nakada; Yusuke Ohba; Hideyuki Nakagawa

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Hideyuki Nakagawa

Takeda Pharmaceutical Company

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Tetsuya Tsukamoto

Takeda Pharmaceutical Company

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Hiroshi Miki

Takeda Pharmaceutical Company

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Koki Kato

Takeda Pharmaceutical Company

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Masaki Ogino

Takeda Pharmaceutical Company

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Mitsuyuki Shimada

Takeda Pharmaceutical Company

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Norikazu Tamura

Takeda Pharmaceutical Company

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Shogo Marui

Takeda Pharmaceutical Company

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Taisuke Katoh

Takeda Pharmaceutical Company

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Toshihiro Yamamoto

Takeda Pharmaceutical Company

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