Wataru Hamaguchi
Astellas Pharma
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Publication
Featured researches published by Wataru Hamaguchi.
Bioorganic & Medicinal Chemistry | 2013
Wataru Hamaguchi; Naoyuki Masuda; Mai Isomura; Satoshi Miyamoto; Shigetoshi Kikuchi; Yasushi Amano; Kazuya Honbou; Takuma Mihara; Toshihiro Watanabe
A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1.
Bioorganic & Medicinal Chemistry | 2012
Kenji Negoro; Yasuhiro Yonetoku; Hana Misawa-Mukai; Wataru Hamaguchi; Tatsuya Maruyama; Shigeru Yoshida; Makoto Takeuchi; Mitsuaki Ohta
Novel 4-amino-2-phenylpyrimidine derivatives were synthesized and evaluated as GPR119 agonists. Optimization of the substituents on the phenyl ring at the 2-position and the amino group at the 4-position led to the identification of 3,4-dihalogenated and 2,4,5-trihalogenated phenyl derivatives showing potent GPR119 agonistic activity. The advanced analog (2R)-3-{[2-(4-chloro-2,5-difluorophenyl)-6-ethylpyrimidin-4-yl]amino}propane-1,2-diol (24g) was found to improve glucose tolerance at 1mg/kg po in mice and to show excellent pharmacokinetic profiles in mice and monkeys. Compound 24g also showed an excellent antidiabetic effect in diabetic kk/Ay mice after one week of single daily treatment. These results demonstrate that novel GPR119 agonist 24g improves glucose tolerance not only by enhancing glucose-dependent insulin secretion but also by preserving pancreatic β-cell function.
Bioorganic & Medicinal Chemistry | 2015
Wataru Hamaguchi; Naoyuki Masuda; Satoshi Miyamoto; Yasuhiro Shiina; Shigetoshi Kikuchi; Takuma Mihara; Hiroyuki Moriguchi; Hiroshi Fushiki; Yoshihiro Murakami; Yasushi Amano; Kazuya Honbou; Kouji Hattori
A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.
Bioorganic & Medicinal Chemistry | 2012
Takashi Sugane; Takahiko Tobe; Wataru Hamaguchi; Itsuro Shimada; Kyoichi Maeno; Junji Miyata; Takeshi Suzuki; Tetsuya Kimizuka; Takuma Morita; Shuichi Sakamoto; Shin-ichi Tsukamoto
To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
Bioorganic & Medicinal Chemistry | 2015
Wataru Hamaguchi; Naoyuki Masuda; Satoshi Miyamoto; Shigetoshi Kikuchi; Fumie Narazaki; Yasuhiro Shiina; Ryushi Seo; Yasushi Amano; Takuma Mihara; Hiroyuki Moriguchi; Kouji Hattori
We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.
Bioorganic & Medicinal Chemistry | 2009
Kazuhiro Yokoyama; Noriko Ishikawa; Susumu Igarashi; Noriyuki Kawano; Naoyuki Masuda; Wataru Hamaguchi; Shingo Yamasaki; Yohei Koganemaru; Kazuyuki Hattori; Takahiro Miyazaki; Shin-ichi Ogino; Yuzo Matsumoto; Makoto Takeuchi; Mitsuaki Ohta
Archive | 2004
Wataru Hamaguchi; Koji Kato; Yohei Koganemaru; Noriyuki Kono; Naoyuki Masuda; Takahiro Miyazaki; 浩二 加藤; 直之 増田; 宇広 宮▲ざき▼; 陽平 小金丸; 則征 河野
Chemical & Pharmaceutical Bulletin | 2014
Wataru Hamaguchi; Naoyuki Masuda; Kiyohiro Samizu; Takuma Mihara; Kaori Takama; Toshihiro Watanabe
Tetrahedron-asymmetry | 2012
Takashi Sugane; Noritaka Hamada; Takahiko Tobe; Wataru Hamaguchi; Itsuro Shimada; Kyoichi Maeno; Junji Miyata; Takeshi Suzuki; Tetsuya Kimizuka; Shuichi Sakamoto; Shin-ichi Tsukamoto
Archive | 2010
Isao Kinoyama; Takehiro Miyazaki; Yohei Koganemaru; Takuya Washio; Wataru Hamaguchi