Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists

Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect

Nagaaki Sato, Makoto Ando, Shiho Ishikawa, Makoto Jitsuoka, Keita Nagai, Hirobumi Takahashi, Aya Sakuraba, Hiroyasu Tsuge, Hidefumi Kitazawa, Hisashi Iwaasa, Satoshi Mashiko, Akira Gomori, Ryuichi Moriya, Naoko Fujino, Tomoyuki Ohe, Akane Ishihara, Akio Kanatani, Takehiro Fukami

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp34NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

Original languageEnglish
Pages (from-to)3385-3396
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number10
DOIs
Publication statusPublished - 2009 May 28
Externally publishedYes

Fingerprint

Neuropeptide Y Receptors
Imidazolines
Potassium Channels
Ether
Genes
Obese Mice
Oral Administration
Permeability
Pharmacokinetics
Eating
Body Weight
Diet
Brain
neuropeptide Y5 receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists : Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect. / Sato, Nagaaki; Ando, Makoto; Ishikawa, Shiho; Jitsuoka, Makoto; Nagai, Keita; Takahashi, Hirobumi; Sakuraba, Aya; Tsuge, Hiroyasu; Kitazawa, Hidefumi; Iwaasa, Hisashi; Mashiko, Satoshi; Gomori, Akira; Moriya, Ryuichi; Fujino, Naoko; Ohe, Tomoyuki; Ishihara, Akane; Kanatani, Akio; Fukami, Takehiro.

In: Journal of Medicinal Chemistry, Vol. 52, No. 10, 28.05.2009, p. 3385-3396.

Research output: Contribution to journalArticle

Sato, N, Ando, M, Ishikawa, S, Jitsuoka, M, Nagai, K, Takahashi, H, Sakuraba, A, Tsuge, H, Kitazawa, H, Iwaasa, H, Mashiko, S, Gomori, A, Moriya, R, Fujino, N, Ohe, T, Ishihara, A, Kanatani, A & Fukami, T 2009, 'Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect', Journal of Medicinal Chemistry, vol. 52, no. 10, pp. 3385-3396. https://doi.org/10.1021/jm900110t
Sato, Nagaaki ; Ando, Makoto ; Ishikawa, Shiho ; Jitsuoka, Makoto ; Nagai, Keita ; Takahashi, Hirobumi ; Sakuraba, Aya ; Tsuge, Hiroyasu ; Kitazawa, Hidefumi ; Iwaasa, Hisashi ; Mashiko, Satoshi ; Gomori, Akira ; Moriya, Ryuichi ; Fujino, Naoko ; Ohe, Tomoyuki ; Ishihara, Akane ; Kanatani, Akio ; Fukami, Takehiro. / Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists : Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 10. pp. 3385-3396.
@article{6b732a69a52a4e778d33339fce22f7f2,
title = "Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect",
abstract = "A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp34NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.",
author = "Nagaaki Sato and Makoto Ando and Shiho Ishikawa and Makoto Jitsuoka and Keita Nagai and Hirobumi Takahashi and Aya Sakuraba and Hiroyasu Tsuge and Hidefumi Kitazawa and Hisashi Iwaasa and Satoshi Mashiko and Akira Gomori and Ryuichi Moriya and Naoko Fujino and Tomoyuki Ohe and Akane Ishihara and Akio Kanatani and Takehiro Fukami",
year = "2009",
month = "5",
day = "28",
doi = "10.1021/jm900110t",
language = "English",
volume = "52",
pages = "3385--3396",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists

T2 - Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect

AU - Sato, Nagaaki

AU - Ando, Makoto

AU - Ishikawa, Shiho

AU - Jitsuoka, Makoto

AU - Nagai, Keita

AU - Takahashi, Hirobumi

AU - Sakuraba, Aya

AU - Tsuge, Hiroyasu

AU - Kitazawa, Hidefumi

AU - Iwaasa, Hisashi

AU - Mashiko, Satoshi

AU - Gomori, Akira

AU - Moriya, Ryuichi

AU - Fujino, Naoko

AU - Ohe, Tomoyuki

AU - Ishihara, Akane

AU - Kanatani, Akio

AU - Fukami, Takehiro

PY - 2009/5/28

Y1 - 2009/5/28

N2 - A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp34NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

AB - A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp34NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

UR - http://www.scopus.com/inward/record.url?scp=66249142634&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66249142634&partnerID=8YFLogxK

U2 - 10.1021/jm900110t

DO - 10.1021/jm900110t

M3 - Article

VL - 52

SP - 3385

EP - 3396

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 10

ER -