Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists

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• 作者：Shuanghua Hu ; Yazhong Huang ; Milind Deshpande ; Guanglin Luo ; Marc A. Bruce ; Ling Chen ; Gail Mattson ; Lawrence G. Iben ; Jie Zhang ; John W. Russell ; Wendy J. Clarke ; John B. Hogan ; Astrid Ortiz ; Oliver Flint ; Andrew Henwood ; Qi Gao ; Ildiko Antal-Zimanyi ; Graham S. Poindexter
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：3
• 期：3
• 页码：222-226
• 全文大小：277K
• 年卷期：v.3,no.3(March 8, 2012)
• ISSN：1948-5875

文摘

A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [¹²⁵I]PYY binding to the Y1 receptor. The most potent member, 1-((1伪,3伪,5伪,6尾)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC₅₀ = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague鈥揇awley rats, 2 significantly reduced food intake during a 12 h period.

Keywords:

bicyclo[3.1.0]hexanylpiperazines; noncompetitive neuropeptide Y Y1 antagonists; brain penetration