1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective norepinephrine reuptake inhibitors.

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Vu AT, Cohn ST, Zhang P, Kim CY, Mahaney PE, Bray JA, Johnston GH, Koury EJ, Cosmi SA, Deecher DC, Smith VA, Harrison JE, Leventhal L, Whiteside GT, Kennedy JD, Trybulski EJ

1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective norepinephrine reuptake inhibitors.

J Med Chem. 2010 Mar 11;53(5):2051-62. doi: 10.1021/jm901559e.

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20131864 [ View in PubMed

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Abstract

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 (IC(50) = 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Desipramine	Sodium-dependent noradrenaline transporter	IC 50 (nM)	3.4	N/A	N/A	Details
Desipramine	Sodium-dependent noradrenaline transporter	IC 50 (nM)	3.3	N/A	N/A	Details
Fluoxetine	Sodium-dependent serotonin transporter	IC 50 (nM)	9.4	N/A	N/A	Details