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Dive into the research topics where Hidekazu Tokuhara is active.

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Featured researches published by Hidekazu Tokuhara.


ACS Medicinal Chemistry Letters | 2016

Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor

Yasuhiro Imaeda; Hidekazu Tokuhara; Yoshiyuki Fukase; Ray Kanagawa; Yumiko Kajimoto; Keiji Kusumoto; Mitsuyo Kondo; Gyorgy Snell; Craig A. Behnke; Takanobu Kuroita

The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1′ site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.


Bioorganic & Medicinal Chemistry | 2018

Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile

Hidekazu Tokuhara; Yasuhiro Imaeda; Yoshiyuki Fukase; Koichi Iwanaga; Naohiro Taya; Koji Watanabe; Ray Kanagawa; Keisuke Matsuda; Yumiko Kajimoto; Keiji Kusumoto; Mitsuyo Kondo; Gyorgy Snell; Craig A. Behnke; Takanobu Kuroita

We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.


Bioorganic & Medicinal Chemistry | 2018

Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives

Mitsunori Kono; Tsuneo Oda; Michiko Tawada; Takashi Imada; Yoshihiro Banno; Naohiro Taya; Tetsuji Kawamoto; Hidekazu Tokuhara; Yoshihide Tomata; Naoki Ishii; Atsuko Ochida; Yoshiyuki Fukase; Tomoya Yukawa; Shoji Fukumoto; Hiroyuki Watanabe; Keiko Uga; Akira Shibata; Hideyuki Nakagawa; Mikio Shirasaki; Yasushi Fujitani; Masashi Yamasaki; Junya Shirai; Satoshi Yamamoto

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.


Archive | 2008

Substituted imidazole compound and use thereof

Takanobu Kuroita; Tsuneo Oda; Yasutomi Asano; Naohiro Taya; Kouichi Iwanaga; Hidekazu Tokuhara; Yoshiyuki Fukase


Archive | 2011

FUSED HETEROCYCLIC COMPOUND AND APPLICATION THEREOF

Nobuyuki Matsunaga; Hideo Suzuki; Kouhei Asano; Hidekazu Tokuhara; Takeshi Yamamoto; Rei Okamoto


Journal of Medicinal Chemistry | 2018

Discovery of [cis-3-({(5R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

Mitsunori Kono; Atsuko Ochida; Tsuneo Oda; Takashi Imada; Yoshihiro Banno; Naohiro Taya; Shinichi Masada; Tetsuji Kawamoto; Kazuko Yonemori; Yoshi Nara; Yoshiyuki Fukase; Tomoya Yukawa; Hidekazu Tokuhara; Robert J. Skene; Bi-Ching Sang; Isaac D. Hoffman; Gyorgy Snell; Keiko Uga; Akira Shibata; Keiko Igaki; Yoshiki Nakamura; Hideyuki Nakagawa; Noboru Tsuchimori; Masashi Yamasaki; Junya Shirai; Satoshi Yamamoto


Archive | 2017

HETEROCYCLIC COMPOUNDS AND THEIR USE AS RETINOID-RELATED ORPHAN RECEPTOR (ROR) GAMMA-T INHIBITORS

Satoshi Yamamoto; Junya Shirai; Tsuneo Oda; Mitsunori Kono; Atsuko Ochida; Takashi Imada; Hidekazu Tokuhara; Yoshihide Tomata; Naoki Ishii; Michiko Tawada; Yoshiyuki Fukase; Tomoya Yukawa; Shoji Fukumoto


Archive | 2016

COMPUESTOS HETEROCÍCLICOS, INHIBIDORES DE RORgt

Shoji Fukumoto; Tomoya Yukawa; Yoshiyuki Fukase; Michiko Tawada; Naoki Ishii; Yoshihide Tomata; Hidekazu Tokuhara; Takashi Imada; Atsuko Ochida; Mitsunori Kono; Tsuneo Oda; Junya Shirai; Satoshi Yamamoto


Archive | 2015

4-(PIPERRAZIN-1-YL)-PYRROLIDIN-2-ONE COMPOUNDS AS MONOACYLGLYCEROL LIPASE (MAGL) INHIBITORS

Tatsuki Koike; Makoto Fushimi; Jumpei Aida; Shuhei Ikeda; Tomokazu Kusumoto; Hideyuki Sugiyama; Hidekazu Tokuhara


Archive | 2011

Substituted pyrido[2,3-d]pyrimidines as delta-5-desaturase inhibitors

Nobuyuki Matsunaga; Hideo Suzuki; Kouhei Asano; Hidekazu Tokuhara; Takeshi Yamamoto; Rei Okamoto

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Yoshiyuki Fukase

Takeda Pharmaceutical Company

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Naohiro Taya

Takeda Pharmaceutical Company

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Takanobu Kuroita

Takeda Pharmaceutical Company

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Tsuneo Oda

Takeda Pharmaceutical Company

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Kouichi Iwanaga

Takeda Pharmaceutical Company

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Atsuko Ochida

Takeda Pharmaceutical Company

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Junya Shirai

Takeda Pharmaceutical Company

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Mitsunori Kono

Takeda Pharmaceutical Company

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Satoshi Yamamoto

Takeda Pharmaceutical Company

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Takashi Imada

Takeda Pharmaceutical Company

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