Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).
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O'Neill DJ, Adedoyin A, Alfinito PD, Bray JA, Cosmi S, Deecher DC, Fensome A, Harrison J, Leventhal L, Mann C, McComas CC, Sullivan NR, Spangler TB, Uveges AJ, Trybulski EJ, Whiteside GT, Zhang P
Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).
J Med Chem. 2010 Jun 10;53(11):4511-21. doi: 10.1021/jm100053t.
- PubMed ID
- 20462211 [ View in PubMed]
- Abstract
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Desipramine Sodium-dependent noradrenaline transporter Ki (nM) 2.1 N/A N/A Details Desipramine Sodium-dependent noradrenaline transporter Ki (nM) 3.4 N/A N/A Details Fluoxetine Sodium-dependent serotonin transporter IC 50 (nM) 9.4 N/A N/A Details Mazindol Sodium-dependent dopamine transporter Ki (nM) 22.1 N/A N/A Details