title: Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives with N-Arylalkynyl Substituents.
abstract: 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 (pKi) of 7.61±0.03 to mGAT1 and uptake inhibition (pIC50) 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 pKi=8.33±0.01, and the uptake inhibitory potency up to pIC50=7.72±0.02.
authors.affiliation: Department for Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Lutz
authors.affiliation: Department for Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wein
authors.affiliation: Department for Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.affiliation: Department for Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D001665:Binding Sites; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009557:Nipecotic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids; D020033:Protein Isoforms
keywords: GABA uptake inhibitors; cross-coupling reactions; molecular modeling; nipecotic acid; structure-activity relationships