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.
Synthesis and biological evaluation of new non-imidazole H(3)-receptor antagonists of the 2-aminobenzimidazole series / Rivara, Mirko; Zuliani, Valentina; Cocconcelli, G; Morini, Giovanni; Comini, Mara; Rivara, Silvia; Mor, Marco; Bordi, Fabrizio; Barocelli, Elisabetta; Ballabeni, Vigilio; Bertoni, Simona; Plazzi, Pier Vincenzo. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 14:(2006), pp. 1413-1424. [10.1016/j.bmc.2005.09.063]
Synthesis and biological evaluation of new non-imidazole H(3)-receptor antagonists of the 2-aminobenzimidazole series
RIVARA, Mirko;ZULIANI, Valentina;MORINI, Giovanni;COMINI, Mara;RIVARA, Silvia;MOR, Marco;BORDI, Fabrizio;BAROCELLI, Elisabetta;BALLABENI, Vigilio;BERTONI, Simona;PLAZZI, Pier Vincenzo
2006-01-01
Abstract
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.File | Dimensione | Formato | |
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