2. Academic Validation
  3. Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152)

Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152)

  • J Med Chem. 2011 Oct 13;54(19):6824-31. doi: 10.1021/jm200733r.
David J O'Neill 1,  Adedayo Adedoyin,  Jenifer A Bray,  Darlene C Deecher,  Andrew Fensome,  Joel A Goldberg,  Jim Harrison,  Liza Leventhal,  Charles Mann,  Lilly Mark,  Lisa Nogle,  Nicole R Sullivan,  Taylor B Spangler,  Eugene A Terefenko,  Eugene J Trybulski,  Albert J Uveges,  An Vu,  Garth T Whiteside,  Puwen Zhang
Affiliations

Affiliation

  • 1 Chemical Sciences, Pfizer, 500 Arcola Road, Collegeville, Pennsylvania 19426, United States. [email protected]
PMID: 21916421 DOI: 10.1021/jm200733r
Abstract

Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.

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