Hiroshi Imoto
Takeda Pharmaceutical Company
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Featured researches published by Hiroshi Imoto.
Bioorganic & Medicinal Chemistry | 2012
Kentaro Rikimaru; Takeshi Wakabayashi; Hidenori Abe; Hiroshi Imoto; Tsuyoshi Maekawa; Osamu Ujikawa; Katsuhito Murase; Takanori Matsuo; Mitsuharu Matsumoto; Chisako Nomura; Hiroko Tsuge; Naoto Arimura; Kazutoshi Kawakami; Junichi Sakamoto; Miyuki Funami; Clifford D. Mol; Gyorgy Snell; Kenneth A. Bragstad; Bi-Ching Sang; Douglas R. Dougan; Toshimasa Tanaka; Nozomi Katayama; Yoshiaki Horiguchi; Yu Momose
Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) γ agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARγ ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid-based agonist 1 and acylsulfonamide 3d.
Bioorganic & Medicinal Chemistry | 2014
Kenjiro Sato; Hiromichi Sugimoto; Kentaro Rikimaru; Hiroshi Imoto; Masahiro Kamaura; Nobuyuki Negoro; Yoshiyuki Tsujihata; Hirohisa Miyashita; Tomoyuki Odani; Toshiki Murata
GPR119 has emerged as an attractive target for anti-diabetic agents. We identified a structurally novel GPR119 agonist 22c that carries a 5-(methylsulfonyl)indoline motif as an early lead compound. To generate more potent compounds of this series, structural modifications were performed mainly to the central alkylene spacer. Installation of a carbonyl group and a methyl group on this spacer significantly enhanced agonistic activity, resulting in the identification of 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]propyl 7-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indole-1-carboxylate (20). To further expand the chemical series of indoline-based GPR119 agonists, several heterocyclic core systems were introduced as surrogates of the carbamate spacer that mimic the presumed active conformation. This approach successfully produced an indolinylpyrimidine derivative 37, 5-(methylsulfonyl)-1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2,3-dihydro-1H-indole, which has potent GPR119 agonist activity. In rat oral glucose tolerance tests, these two indoline-based compounds effectively lowered plasma glucose excursion and glucose-dependent insulin secretion after oral administration.
Bioorganic & Medicinal Chemistry | 2012
Kentaro Rikimaru; Takeshi Wakabayashi; Hidenori Abe; Taisuke Tawaraishi; Hiroshi Imoto; Jinichi Yonemori; Hideki Hirose; Katsuhito Murase; Takanori Matsuo; Mitsuharu Matsumoto; Chisako Nomura; Hiroko Tsuge; Naoto Arimura; Kazutoshi Kawakami; Junichi Sakamoto; Miyuki Funami; Clifford D. Mol; Gyorgy Snell; Kenneth A. Bragstad; Bi-Ching Sang; Douglas R. Dougan; Toshimasa Tanaka; Nozomi Katayama; Yoshiaki Horiguchi; Yu Momose
In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.
Journal of Medicinal Chemistry | 2000
Mitsuru Shiraishi; Yoshio Aramaki; Masaki Seto; Hiroshi Imoto; Youichi Nishikawa; Naoyuki Kanzaki; Mika Okamoto; Hidekazu Sawada; Osamu Nishimura; and Masanori Baba; Masahiko Fujino
Archive | 1999
Y U Momose; Hiroyuki Odaka; Hiroshi Imoto; Hiroyuki Kimura; Junichi Sakamoto
Archive | 2008
Taisuke Tawaraishi; Hiroshi Imoto; Nobuo Cho
Archive | 2005
Yoshiaki Horiguchi; Hiroshi Imoto; Mark A. Wolf
Archive | 2010
Kentaro Rikimaru; Hiroshi Imoto; Masahiro Kamaura
Archive | 2002
Y U Momose; Tsuyoshi Maekawa; Hiroshi Imoto; Hiroyuki Odaka; Hiroyuki Kimura
Chemical & Pharmaceutical Bulletin | 2004
Masaki Seto; Yoshio Aramaki; Hiroshi Imoto; Katsuji Aikawa; Tsuneo Oda; Naoyuki Kanzaki; Yuji Iizawa; Masanori Baba; Mitsuru Shiraishi