1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: Potent, Selective, and Orally Efficacious Norepinephrine Reuptake Inhibitors

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• 作者：Puwen Zhang ; Eugene A. Terefenko ; Jenifer Bray ; Darlene Deecher ; Andrew Fensome ; Jim Harrison ; Callain Kim ; Elizabeth Koury ; Lilly Mark ; Casey C. McComas ; Cheryl A. Mugford ; Eugene J. Trybulski ; An T.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 24, 2009
• 年：2009
• 卷：52
• 期：18
• 页码：5703-5711
• 全文大小：869K
• 年卷期：v.52,no.18(September 24, 2009)
• ISSN：1520-4804

文摘

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19−22) had low nonamolar hNET potency with IC<sub>50sub> values of 7−10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3−10 mg/kg.