title: Synthesis and biological evaluation of a series of N-alkylated imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors.
abstract: In this paper, we report the synthesis and biological evaluation of a series of 1,5- and 1,4- substituted derivatives of 1H-imidazol-4-ylacetic acid, a series of 1,2-substituted 3-(1H-imidazol-2-yl)propanoic acid and an N-substituted (2E)-3-(1H-imidazol-2-yl)prop-2-enoic acid as new mGAT3 inhibitors. The lipophilic moieties attached to the N-atom of the parent structures were delineated from the 2-[9-(4-methoxyphenyl)-9H-fluoren-9-yl]oxyethyl residue, known from a prototypic mGAT3 inhibitor. For the structure-activity-relationship studies, the spacer between the N-atom of the imidazole ring and the 2-[9-(4-methoxyphenyl)-9H-fluoren-9-yl] moiety was varied in length from three to six atoms, and in nature being either a pure saturated or unsaturated alkyl chain or an alkyl chain containing up to two ether functions. The compounds were characterized for inhibitory potencies at mouse GABA transporter proteins mGAT1-mGAT4. Among the 1,2-substituted compounds, the N-alkylated (2E)-3-(1H-imidazol-2-yl)prop-2-enoic acid 12e containing a C5O spacer exhibits a pIC50value of 5.13 ± 0.04 at mGAT3, but is devoid of significant selectivity for this GABA transporter. However, the inhibitory potency displayed by 12e at mGAT3 nominally surpasses that of SNAP-5294 reported as the most potent inhibitor of mGAT3 so far.
authors.affiliation: Ludwig-Maximilians-Universität München, Department für Pharmazie - Zentrum für Pharmaforschung, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kerscher-Hack
authors.affiliation: Ludwig-Maximilians-Universität München, Department für Pharmazie - Zentrum für Pharmaforschung, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Thejavathi
authors.initials: T
authors.lastname: Renukappa-Gutke
authors.affiliation: Ludwig-Maximilians-Universität München, Department für Pharmazie - Zentrum für Pharmaforschung, Butenandtstr. 5-13, 81377, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.affiliation: Ludwig-Maximilians-Universität München, Department für Pharmazie - Zentrum für Pharmaforschung, Butenandtstr. 5-13, 81377, Munich, Germany. Electronic address: klaus.wanner@cup.uni-muenchen.de.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000478:Alkylation; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D058805:GABA Uptake Inhibitors; D007093:Imidazoles; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase
keywords: GABA uptake; N-alkylimidazolealkanoic acids; mGAT3