4-Benzyl-1H-imidazoles with Oxazoline Termini as Histamine H3 Receptor Agonists

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• 作者：Maikel Wijtmans ; Sylvain Celanire ; Erwin Snip ; Michel R. Gillard ; Edith Gelens ; Philippe P. Collart ; Bastiaan J. Venhuis ; Bernard Christophe ; Saskia Hulscher ; Henk van der Goot ; Florence Lebon ; Henk T
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 22, 2008
• 年：2008
• 卷：51
• 期：10
• 页码：2944 - 2953
• 全文大小：720K
• 年卷期：v.51,no.10(May 22, 2008)
• ISSN：1520-4804

文摘

Research on the therapeutic applications of the histamine H₃ receptor (H₃R) has traditionally focused on antagonists/inverse agonists. In contrast, H₃R agonists have received less attention despite their potential use in several disease areas. The lower availability of H₃R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H₃R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H₃R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12−31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H₃R activation and reveal the oxazolino group as a hitherto unexplored functional group in H₃R research.