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.

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.

MeSH terms

  • GABA Plasma Membrane Transport Proteins / chemistry*
  • GABA Plasma Membrane Transport Proteins / metabolism
  • GABA Uptake Inhibitors / chemical synthesis*
  • GABA Uptake Inhibitors / chemistry
  • GABA Uptake Inhibitors / pharmacology
  • Nipecotic Acids / chemical synthesis*
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Nipecotic Acids