Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile

被引：9

作者：

Tamura, Yuusuke ^{[1
]}

Hayashi, Kyouhei ^{[1
]}

Omori, Naoki ^{[1
]}

Nishiura, Yuji ^{[1
]}

Watanabe, Kana ^{[1
]}

Tanaka, Nobuyuki ^{[1
]}

Fujioka, Masahiko ^{[1
]}

Kouyama, Naoki ^{[1
]}

Yukimasa, Akira ^{[1
]}

Tanaka, Yukari ^{[2
]}

Chiba, Takeshi ^{[3
]}

Tanioka, Hideki ^{[1
]}

Nambu, Hirohide ^{[1
]}

Yukioka, Hideo ^{[1
]}

Sato, Hiroki ^{[1
]}

Okuno, Takayuki ^{[1
]}

机构：

[1] Shionogi & Co Ltd, Med Res Labs, Toyonaka, Osaka 5610825, Japan

[2] Shionogi & Co Ltd, Drug Dev Res Labs, Toyonaka, Osaka 5610825, Japan

[3] Shionogi & Co Ltd, Innovat Drug Discovery Res Labs, Toyonaka, Osaka 5610825, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 01期

关键词：

Obesity; NPY Y5 receptor antagonist; GPCR; Benzimidazole; Gauche effect; NEUROPEPTIDE-Y; WEIGHT-LOSS; PEPTIDE-YY; MECHANISMS; EFFICACY; LIGANDS; OBESITY; DESIGN;

D O I：

10.1016/j.bmcl.2012.11.005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：90 / 95

页数：6

共 27 条

[1]

Adrian T.E., 1983, NATURE, V306, P585

[2] Y-receptor subtypes - How many more? [J].

Blomqvist, AG ;

Herzog, H .

TRENDS IN NEUROSCIENCES, 1997, 20 (07) :294-298

[3] NPY5R antagonism does not augment the weight loss efficacy of orlistat or sibutramine [J].

Erondu, Ngozi ;

Addy, Carol ;

Lu, Kaifeng ;

Mallick, Madhuja ;

Musser, Bret ;

Gantz, Ira ;

Proietto, Joseph ;

Astrup, Arne ;

Toubro, Soren ;

Rissannen, Aila M. ;

Tonstad, Serena ;

Haynes, William G. ;

Gottesdiener, Keith M. ;

Kaufman, Keith D. ;

Amatruda, John M. ;

Heymsfield, Steven B. .

OBESITY, 2007, 15 (08) :2027-2042

[4] Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults [J].

Erondu, Ngozi ;

Gantz, Ira ;

Musser, Bret ;

Suryawanshi, Shailaja ;

Mallick, Madhuja ;

Addy, Carol ;

Cote, Josee ;

Bray, George ;

Fujioka, Ken ;

Bays, Harold ;

Hollander, Priscilla ;

Sanabria-Bohorquez, Sandra M. ;

Eng, WaiSi ;

Langstrom, Bengt ;

Hargreaves, Richard J. ;

Burns, H. Donald ;

Kanatani, Akio ;

Fukami, Takehiro ;

MacNeil, Douglas J. ;

Gottesdiener, Keith M. ;

Amatruda, John M. ;

Kaufman, Keith D. ;

Heymsfield, Steven B. .

CELL METABOLISM, 2006, 4 (04) :275-282

[5] Generation of a set of simple, interpretable ADMET rules of thumb [J].

Gleeson, M. Paul .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :817-834

[6] MULTIPLE NEUROPEPTIDE-Y RECEPTORS ARE INVOLVED IN CARDIOVASCULAR REGULATION - PERIPHERAL AND CENTRAL MECHANISMS [J].

GRUNDEMAR, L ;

HAKANSON, R .

GENERAL PHARMACOLOGY-THE VASCULAR SYSTEM, 1993, 24 (04) :785-796

[7] Improvement in Aqueous Solubility in Small Molecule Drug Discovery Programs by Disruption of Molecular Planarity and Symmetry [J].

Ishikawa, Minoru ;

Hashimoto, Yuichi .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (06) :1539-1554

[8] Neuropeptide Y receptor selective ligands in the treatment of obesity [J].

Kamiji, M. M. ;

Inui, A. .

ENDOCRINE REVIEWS, 2007, 28 (06) :664-684

[9] Regulation of maternal food intake and mother-pup interactions by the Y5 receptor [J].

Ladyman, Sharon R. ;

Woodside, Barbara .

PHYSIOLOGY & BEHAVIOR, 2009, 97 (01) :91-97

[10]

Levens N.R., 2006, DRUG TARGETS CNS NEU, V5, P263

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