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
; 53(11): 4511-21, 2010 Jun 10.
Article
en En
| MEDLINE
| ID: mdl-20462211
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Tiadiazoles
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Norepinefrina
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Inhibidores de la Captación de Neurotransmisores
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Óxidos S-Cíclicos
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Descubrimiento de Drogas
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2010
Tipo del documento:
Article