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
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] Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists
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
[3] Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists
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
[4] A potent and selective NPY Y5 antagonist reduces food intake but not through blockade of the NPY Y5 receptor
O Della-Zuana
L Revereault
A Beck-Sickinger
A Monge
D-H Caignard
J-L Fauchère
J-M Henlin
V Audinot
J A Boutin
S Chamorro
M Félétou
N Levens
International Journal of Obesity, 2004, 28 : 628 - 639
[5] Discovery of novel orally active and selective ureido-NPY Y5 antagonists
Li, Guoqing
Huang, Ying
Kelly, Joseph
Stamford, Andrew
Greenlee, William
Mullins, Deborra
Guzzi, Mario
Zhang, Xiaoping
Hwa, Joyce J.
Gao, Jun
Ghibaudi, Lorraine
Weihaus, Sam
Cheng, K. -C.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2005, 230 : U2564 - U2564
[6] Aryl urea derivatives of spiropiperidines as NPY Y5 receptor antagonists
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
[7] A preliminary study of the metabolic stability of a series of benzoxazinone derivatives as potent neuropeptide Y5 antagonists
Dordal, A
Lipkin, M
Macritchie, J
Mas, J
Port, A
Rose, S
Salgado, L
Savic, V
Schmidt, W
Serafini, MT
Spearing, W
Torrens, A
Yeste, S
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (16) : 3679 - 3684
[8] Novel orally active NPY Y5 receptor antagonists: Synthesis and structure-activity relationship of spiroindoline class compounds
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
[9] Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist
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
[10] Synthesis and evaluation of 5,5-diphenylimidazolones as potent human neuropeptide Y5 receptor antagonists
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

← 1 2 3 4 5 →