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.

David J O'Neill ¹, Adedayo Adedoyin, Peter D Alfinito, Jenifer A Bray, Scott Cosmi, Darlene C Deecher, Andrew Fensome, Jim Harrison, Liza Leventhal, Charles Mann, Casey C McComas, Nicole R Sullivan, Taylor B Spangler, Albert J Uveges, Eugene J Trybulski, Garth T Whiteside, Puwen Zhang

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Affiliation

1 Chemical Sciences, Pfizer Global Research & Development, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. [email protected]

PMID: 20462211 DOI: 10.1021/jm100053t

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.

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