Stereospecific synthesis and structure-activity relationships of unsymmetrical 4,4-diphenylbut-3-enyl derivatives of nipecotic acid as GAT-1 inhibitors |
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Authors: | Pizzi Domenica A Leslie Colin P Di Fabio Romano Seri Catia Bernasconi Giovanni Squaglia Michela Carnevale Gennaro Falchi Alessandro Greco Elisabetta Mangiarini Laura Negri Michele |
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Institution: | Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Via A Fleming 4, 37135 Verona, Italy. domenica.a.pizzi@gsk.com |
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Abstract: | Two complementary stereospecific synthetic approaches for the preparation of unsymmetrical ortho-substituted N-(4,4-diphenylbut-3-enyl) derivatives of nipecotic acid are described. Determination of the activity of the prepared compounds at the GAT-1 transporter highlighted differing SAR requirements of the E- and Z-phenyl rings, and led to the discovery of a compound with comparable potency to tiagabine. Some attempts to replace nipecotic acid with alternative novel amino acids are also described. |
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