title: Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives by Suzuki-Miyaura Cross-Coupling Reactions.
abstract: A new series of potent and selective mGAT1 inhibitors has been identified, featuring a nipecotic acid residue and an N-butenyl linker with a 2-biphenyl residue at the ω-position. Docking, combined with MD calculations, revealed a binding mode for the new compounds similar to that of tiagabine, the only mGAT1 inhibitor currently approved as antiepileptic drug. For the synthesis, a Suzuki-Miyaura cross-coupling reaction was used as a key step by which variously substituted biaryl subunits were assembled. Biological evaluation revealed several compounds that possess binding affinities and inhibitory potencies toward mGAT1, together with subtype selectivities against mGAT2-mGAT4 that were similar to or even higher than those for tiagabine. A derivative carrying the 2',4'-dichloro-2-biphenyl moiety attached to N-but-3-enylnipecotic acid at the terminal position of the linker chain was found to be the most potent binder, with the racemic form of the compound displaying a binding affinity of 8.05±0.13 (pKi ), while the R enantiomer exhibited an affinity value of 8.33±0.06 (pKi ).
authors.affiliation: Galliera Hospital, Mura delle Cappuccine 14, 16128, Genova, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Petrera
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwigs-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wein
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwigs-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Allmendinger
authors.affiliation: Department Pharmacology, Weill Cornell Medical College, LC-428 1300 York Avenue, New York, NY, 10021, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sindelar
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwigs-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Pabel
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwigs-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwigs-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany. klaus.wanner@cup.uni-muenchen.de.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000818:Animals; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; C030278:nipecotic acid
keywords: GABA uptake transporters; Suzuki-Miyaura cross-coupling; molecular modeling; nipecotic acid; structure-activity relationships