Synthesis and biological evaluation of new non-imidazole H3-receptor antagonists of the 2-aminobenzimidazole series
| Autor: | Giuseppe Cocconcelli, Mara Comini, Vigilio Ballabeni, Giovanni Morini, Fabrizio Bordi, Marco Mor, Simona Bertoni, Mirko Rivara, Elisabetta Barocelli, Pier Vincenzo Plazzi, Silvia Rivara, Valentina Zuliani |
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| Rok vydání: | 2006 |
| Předmět: |
Benzimidazole
Stereochemistry Clinical Biochemistry Histamine Antagonists Substituent Pharmaceutical Science Ring (chemistry) Biochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Piperidines Drug Discovery Animals Receptors Histamine H3 Moiety Imidazole Molecular Biology Cells Cultured Binding Sites Bicyclic molecule Organic Chemistry Imidazoles Brain Rats chemistry Molecular Medicine Benzimidazoles Piperidine Chlorophenols |
| Zdroj: | Bioorganic & Medicinal Chemistry. 14:1413-1424 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2005.09.063 |
| Popis: | A novel series of non-imidazole H(3)-receptor antagonists was developed, by chemical modification of a potent lead H(3)-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 H(3)-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 H(3)-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 H(3)-antagonist potencies with 2-aminobenzimidazoles having a tertiary amino group at appropriate distance. |
| Databáze: | OpenAIRE |
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