1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as Potent and Selective Norepinephrine Reuptake Inhibitors

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• 作者：An T. Vu ; Stephen T. Cohn ; Puwen Zhang ; Callain Y. Kim ; Paige E. Mahaney ; Jenifer A. Bray ; Grace H. Johnston ; Elizabeth J. Koury ; Scott A. Cosmi ; Darlene C. Deecher ; Valerie A. Smith ; James E. Harriso
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：March 11, 2010
• 年：2010
• 卷：53
• 期：5
• 页码：2051-2062
• 全文大小：915K
• 年卷期：v.53,no.5(March 11, 2010)
• ISSN：1520-4804

文摘

Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure−activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC₅₀ = 2.7−6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.