title: Synthesis and biological evaluation of 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives as GABA uptake inhibitors.
abstract: A series of enantiomerically pure 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives have been synthesized starting from the respective N-protected 4-hydroxy derivatives via oxidation to the corresponding 4-oxo compounds, subsequent addition of organometallic reagents, final hydrolysis and deprotection. The major diastereoisomers obtained by the addition of the Grignard reagents were found to have opposite stereoconfigurations depending on whether cerium trichloride was present or absent as an additive. The final compounds were evaluated for their capability to inhibit the GABA transport proteins GAT1 and GAT3. 4-Hydroxyproline derivatives substituted with a tris(4-methoxyphenyl)methyloxyethyl residue at the nitrogen and a 4-methoxyphenyl group in 4-position showed, with the exception of the (2R,4R)-diastereomer, an improved inhibition at GAT3 compared to the derivatives missing the 4-methoxyphenyl group in 4-position. This may imply that an appropriate lipophilic group at the C-4 position of the proline moiety is beneficial for potent inhibition at GAT3.
authors.affiliation: Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Zhao
authors.forename: Jörg
authors.initials: J
authors.lastname: Pabel
authors.forename: Georg C
authors.initials: GC
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D004353:Drug Evaluation, Preclinical; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D011759:Pyrrolidines; D011392:Proline; C032519:pyrrolidine