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Lutz, Toni; Wein, Thomas; Höfner, Georg; Wanner, Klaus T. (2017): Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives with N-Arylalkynyl Substituents. In: ChemMedChem, Vol. 12, No. 5: pp. 362-371
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A new scaffold of highly potent and mGAT1-selective inhibitors has been developed. Compounds in this class are characterized by an alkyne-type spacer connecting nipecotic acid with an aromatic moiety. Preliminary evaluations made it apparent that a nipecotic acid derivative with an N-butynyl linker and a terminal 2-biphenyl residue exhibiting a binding affinity (pK(i)) of 7.61 +/- 0.03 to mGAT1 and uptake inhibition (pIC(50)) of 7.00 +/- 0.06 selective for mGAT1 could serve as a hit compound. Docking calculations for compounds based on this structure in an hGAT1 homology modeling study indicated binding affinities similar to or even higher than that of the well-known mGAT1 inhibitor tiagabine. Synthesis of the designed compounds was readily carried out by two consecutive cross-coupling reactions, giving flexible access to variously substituted biphenyl subunits. With an appropriate substitution pattern of the biphenyl moiety, the binding affinity of enantiopure (R)-nipecotic acid derivatives to mGAT1 increased to pK(i)=8.33 +/- 0.01, and the uptake inhibitory potency up to pIC(50)=7.72 +/- 0.02.