Premium
Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives with N ‐Arylalkynyl Substituents
Author(s) -
Lutz Toni,
Wein Thomas,
Höfner Georg,
Wanner Klaus T.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600599
Subject(s) - nipecotic acid , moiety , stereochemistry , chemistry , linker , residue (chemistry) , alkyne , lead compound , combinatorial chemistry , biochemistry , in vitro , receptor , computer science , neurotransmitter , catalysis , operating system
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 (p K 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 p K i =8.33±0.01, and the uptake inhibitory potency up to pIC 50 =7.72±0.02.