Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction

被引:56
作者
Cowart, M [1 ]
Latshaw, SP [1 ]
Bhatia, P [1 ]
Daanen, JF [1 ]
Rohde, J [1 ]
Nelson, SL [1 ]
Patel, M [1 ]
Kolasa, T [1 ]
Nakane, M [1 ]
Uchic, ME [1 ]
Miller, LN [1 ]
Terranova, MA [1 ]
Hang, RJ [1 ]
Donnelly-Roberts, DL [1 ]
Namovic, MT [1 ]
Hollingsworth, PR [1 ]
Martino, BR [1 ]
Lynch, JJ [1 ]
Sullivan, JP [1 ]
Hsieh, GC [1 ]
Moreland, RB [1 ]
Brioni, JD [1 ]
Stewart, AO [1 ]
机构
[1] Abbott Labs, Dept Neurosci Res, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/jm030505a
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D-4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D-4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 mumol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D-4 selective agonism in this series of analogues.
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收藏
页码:3853 / 3864
页数:12
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