Synthesis and biological evaluation of new non-imidazole H₃-receptor antagonists of the 2-aminobenzimidazole series

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• 作者：Mirko Rivara ; Valentina Zuliani ; Giuseppe Cocconcelli ; Giovanni Morini ; Mara Comini ; Silvia Rivara ; Marco Mor ; Fabrizio Bordi ; Elisabetta Barocelli ; Vigilio Ballabeni et al.
• 关键词：Histamine ; H₃-receptor antagonists ; 2-Aminobenzimidazole ; Non-imidazole
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：1 March 2006
• 年：2006
• 卷：14
• 期：5
• 页码：1413-1424
• 全文大小：275 K

文摘

A novel series of non-imidazole H₃-receptor antagonists was developed, by chemical modification of a potent lead H₃-antagonist composed by an imidazole ring connected through an alkyl spacer to a 2-aminobenzimidazole moiety (e.g., 2-[[3-[4(5)-imidazolyl]propyl]amino]benzimidazole), previously reported by our research group. We investigated whether the removal of the imidazole ring could allow retaining high affinity for the H₃-receptor, thanks to the interactions undertaken by the 2-aminobenzimidazole moiety at the binding site. The imidazole ring of the lead was replaced by a basic piperidine or by a lipophilic p-chlorophenoxy substituent, modulating the spacer length from three to eight methylene groups; moreover, the substituents were moved to the 5(6) position of the benzimidazole nucleus. Within both the 2-alkylaminobenzimidazole series and the 5(6)-alkoxy-2-aminobenzimidazole one, the greatest H₃-receptor affinity was obtained for the piperidine-substituted compounds, while the presence of the p-chlorophenoxy group resulted in a drop in affinity. The optimal chain length was different in the two series. Even if the new compounds did not reach the high receptor affinity shown by the imidazole-containing lead compound, it was possible to get good H₃-antagonist potencies with 2-aminobenzimidazoles having a tertiary amino group at appropriate distance.