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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Pizzi DA, Leslie CP, Di Fabio R, Seri C, Bernasconi G, Squaglia M, Carnevale G, Falchi A, Greco E, Mangiarini L, Negri M

Stereospecific synthesis and structure-activity relationships of unsymmetrical 4,4-diphenylbut-3-enyl derivatives of nipecotic acid as GAT-1 inhibitors.

Bioorg Med Chem Lett. 2011 Jan 1;21(1):602-5. doi: 10.1016/j.bmcl.2010.09.025. Epub 2010 Sep 15.

PubMed ID

21134748 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tiagabine	Sodium- and chloride-dependent GABA transporter 1	Ki (nM)	16.98	N/A	N/A	Details