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 Antiob

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• 作者：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 Mor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 28, 2009
• 年：2009
• 卷：52
• 期：10
• 页码：3385-3396
• 全文大小：279K
• 年卷期：v.52,no.10(May 28, 2009)
• ISSN：1520-4804

文摘

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.