Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists

被引：5

作者：

Pizzi, Domenica Antonia ^{[1
]}

Leslie, Colin Philip ^{[1
]}

Mazzali, Angelica ^{[1
]}

Seri, Catia ^{[1
]}

Biagetti, Matteo ^{[1
]}

Bentley, Jonathan ^{[1
]}

Genski, Thorsten ^{[1
]}

Di Fabio, Romano ^{[1
]}

Contini, Stefania ^{[1
]}

Sabbatini, Fabio Maria ^{[1
]}

Zonzini, Laura ^{[1
]}

Caberlotto, Laura ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Neurosci Ctr Excellence Drug Discovery, Med Res Ctr, I-37135 Verona, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 23期

关键词：

NPY Y5; Benzimidazoles; NEUROPEPTIDE-Y; RECEPTOR; MECHANISMS; OBESITY;

D O I：

10.1016/j.bmcl.2010.09.064

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30 mg/kg po. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：7120 / 7123

页数：4

共 50 条

[1] Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles [J].

Tamura, Yuusuke ;

Omori, Naoki ;

Kouyama, Naoki ;

Nishiura, Yuji ;

Hayashi, Kyouhei ;

Watanabe, Kana ;

Tanaka, Yukari ;

Chiba, Takeshi ;

Yukioka, Hideo ;

Sato, Hiroki ;

Okuno, Takayuki .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (17) :5498-5502

[2] Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists [J].

Sakamoto, Toshihiro ;

Moriya, Minoru ;

Haga, Yuji ;

Takahashi, Toshiyuki ;

Shibata, Takunobu ;

Okamoto, Osamu ;

Nonoshita, Katsumasa ;

Kitazawa, Hidefumi ;

Hidaka, Masayasu ;

Gomori, Akira ;

Iwaasa, Hisashi ;

Ishihara, Akane ;

Kanatani, Akio ;

Fukami, Takehiro ;

Gao, Ying-Duo ;

MacNeil, Douglas J. ;

Yang, Lihu .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (06) :1564-1568

[3] Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists [J].

Leslie, Colin P. ;

Bentley, Jonathan ;

Biagetti, Matteo ;

Contini, Stefania ;

Di Fabio, Romano ;

Donati, Daniele ;

Genski, Thorsten ;

Guery, Sebastien ;

Mazzali, Angelica ;

Merlo, Giancarlo ;

Pizzi, Domenica A. ;

Sacco, Fabiola ;

Seri, Catia ;

Tessari, Michela ;

Zonzini, Laura ;

Caberlotto, Laura .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (20) :6103-6107

[4] Novel orally active NPY Y5 receptor antagonists: Synthesis and structure-activity relationship of spiroindoline class compounds [J].

Sakamoto, Toshihiro ;

Moriya, Minoru ;

Tsuge, Hiroyasu ;

Takahashi, Toshiyuki ;

Haga, Yuji ;

Nonoshita, Katsumasa ;

Okamoto, Osamu ;

Takahashi, Hirobumi ;

Sakuraba, Aya ;

Hirohashi, Tomoko ;

Shibata, Takunobu ;

Kanno, Tetsuya ;

Ito, Junko ;

Iwaasa, Hisashi ;

Gomori, Akira ;

Ishihara, Akane ;

Fukuroda, Takahiro ;

Kanatani, Akio ;

Fukami, Takehiro .

BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (14) :5015-5026

[5] Aryl urea derivatives of spiropiperidines as NPY Y5 receptor antagonists [J].

Takahashi, Toshiyuki ;

Haga, Yuji ;

Sakamoto, Toshihiro ;

Moriya, Minoru ;

Okamoto, Osamu ;

Nonoshita, Katsumasa ;

Shibata, Takunobu ;

Suga, Takuya ;

Takahashi, Hirobumi ;

Hirohashi, Tomoko ;

Sakuraba, Aya ;

Gomori, Akira ;

Iwaasa, Hisashi ;

Ohe, Tomoyuki ;

Ishihara, Akane ;

Ishii, Yasuyuki ;

Kanatani, Akio ;

Fukami, Takehiro .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (13) :3511-3516

[6] Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile [J].

Tamura, Yuusuke ;

Hayashi, Kyouhei ;

Omori, Naoki ;

Nishiura, Yuji ;

Watanabe, Kana ;

Tanaka, Nobuyuki ;

Fujioka, Masahiko ;

Kouyama, Naoki ;

Yukimasa, Akira ;

Tanaka, Yukari ;

Chiba, Takeshi ;

Tanioka, Hideki ;

Nambu, Hirohide ;

Yukioka, Hideo ;

Sato, Hiroki ;

Okuno, Takayuki .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (01) :90-95

[7] Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist [J].

Omori, Naoki ;

Kouyama, Naoki ;

Yukimasa, Akira ;

Watanabe, Kana ;

Yokota, Yasunori ;

Tanioka, Hideki ;

Nambu, Hirohide ;

Yukioka, Hideo ;

Sato, Norihito ;

Tanaka, Yukari ;

Sekiguchi, Kazutaka ;

Okuno, Takayuki .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (05) :2020-2023

[8] Synthesis and evaluation of 5,5-diphenylimidazolones as potent human neuropeptide Y5 receptor antagonists [J].

Gillman, Kevin W. ;

Higgins, Mendi A. ;

Poindexter, Graham S. ;

Browning, Marc ;

Clarke, Wendy J. ;

Flowers, Sharon ;

Grace, James E., Jr. ;

Hogan, John B. ;

McGovern, Rachel T. ;

Iben, Lawrence G. ;

Mattson, Gail K. ;

Ortiz, Astrid ;

Rassnick, Stefanie ;

Russell, John W. ;

Antal-Zimanyi, Ildiko .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (16) :5517-5526

[9] Identification of a novel and orally available benzimidazole derivative as an NPY Y5 receptor antagonist with in vivo efficacy [J].

Tamura, Yuusuke ;

Omori, Naoki ;

Kouyama, Naoki ;

Nishiura, Yuji ;

Hayashi, Kyouhei ;

Watanabe, Kana ;

Tanaka, Yukari ;

Chiba, Takeshi ;

Yukioka, Hideo ;

Sato, Hiroki ;

Okuno, Takayuki .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (21) :6554-6558

[10] A novel range based QSAR study of human neuropeptide Y (NPY) Y5 receptor inhibitors [J].

Deswal, Sumit ;

Roy, Nilanjan .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2007, 42 (04) :463-470

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