Development of new GABA uptake inhibitors derived from proline or from pyrrolidin-2-yl acetic acid
type: CreativeWork
description: GABA transporters GAT-1, GAT-2 and GAT-3 are new targets for drug design. The substitution of the nitrogen atoms in Nicopetic acid (11), Guvacine (12) and cis-4- Hydroxynicopetic acid (13) with appropriate bulky lipophilic groups resulted in very potent GABA uptake inhibitors for GAT-1 as well as for GAT-3. Pyrrolidine-2-acetic acid derivatives with the three N-substituents 24a-c (Scheme 54) also showed a highly potent inhibition at GAT-1 and GAT-3, respectively. My intention was to investigate how the potency of pyrrolindine-2-carboxylic acid derivatives and of pyrrolidine-2-acetic acid derivatives at GAT-1 and GAT-3 is influenced by the introduction of a hydroxy group or both of a hydroxy and a (4-methoxy)phenyl group at C-4. For this study, the N-substituents 24a-d were chosen. Thus, the four series of pyrrolidine derivatives 20-23 shown below were designed as potential GABA uptake inhibitors. L-trans-4-hydroxypyrrolidine [(2S,4R)-25] was chosen as a precursor, from which the four key intermediates (2S,4R)-38, (2R,4R)-38, (2S,4R)-86 and (2R,4R)-64 were synthesized. The known compounds (2S,4R)-38 and (2R,4R)-38 were prepared from (2S,4R)-25 according to literature procedures. N-protection of (2S,4R)-25 with Cbz group gave (2S,4R)-58 (90% yield). After a series of reactions  electrolysis (97% yield), O-silyl protection (85%), nucleophilic addition of 1- ethoxy-1-(trimethylsilyloxy)ethene (cis-71 79%; trans-71 9%) and finally O-deprotection (88%) and N-deprotection (89%)  (2R,4R)-64 was obtained in 46% overall yield [from (2S,4R)-25]. After the reaction conditions for the conversion of 70 into 71 have been optimized, the best stereoselectivity [a ratio of cis/trans 97:3; yield cis-71 74%, trans-(2S,4R)-71 1.7%] and a good yield of 88% (cis 79%, trans 9%) were achieved. BF3⋅Et2O appeared to be slightly better for a higher stereoselectivity than TiCl4. (2S,4R)-83 was obtained in 90% yield by protecting the hydroxy group of (2S,4R)-58. An Arndt-Eistert reaction (64% …
abstract: GABA transporters GAT-1, GAT-2 and GAT-3 are new targets for drug design. The substitution of the nitrogen atoms in Nicopetic acid (11), Guvacine (12) and cis-4- Hydroxynicopetic acid (13) with appropriate bulky lipophilic groups resulted in very potent GABA uptake inhibitors for GAT-1 as well as for GAT-3. Pyrrolidine-2-acetic acid derivatives with the three N-substituents 24a-c (Scheme 54) also showed a highly potent inhibition at GAT-1 and GAT-3, respectively. My intention was to investigate how the potency of pyrrolindine-2-carboxylic acid derivatives and of pyrrolidine-2-acetic acid derivatives at GAT-1 and GAT-3 is influenced by the introduction of a hydroxy group or both of a hydroxy and a (4-methoxy)phenyl group at C-4. For this study, the N-substituents 24a-d were chosen. Thus, the four series of pyrrolidine derivatives 20-23 shown below were designed as potential GABA uptake inhibitors. L-trans-4-hydroxypyrrolidine [(2S,4R)-25] was chosen as a precursor, from which the four key intermediates (2S,4R)-38, (2R,4R)-38, (2S,4R)-86 and (2R,4R)-64 were synthesized. The known compounds (2S,4R)-38 and (2R,4R)-38 were prepared from (2S,4R)-25 according to literature procedures. N-protection of (2S,4R)-25 with Cbz group gave (2S,4R)-58 (90% yield). After a series of reactions  electrolysis (97% yield), O-silyl protection (85%), nucleophilic addition of 1- ethoxy-1-(trimethylsilyloxy)ethene (cis-71 79%; trans-71 9%) and finally O-deprotection (88%) and N-deprotection (89%)  (2R,4R)-64 was obtained in 46% overall yield [from (2S,4R)-25]. After the reaction conditions for the conversion of 70 into 71 have been optimized, the best stereoselectivity [a ratio of cis/trans 97:3; yield cis-71 74%, trans-(2S,4R)-71 1.7%] and a good yield of 88% (cis 79%, trans 9%) were achieved. BF3⋅Et2O appeared to be slightly better for a higher stereoselectivity than TiCl4. (2S,4R)-83 was obtained in 90% yield by protecting the hydroxy group of (2S,4R)-58. An Arndt-Eistert reaction (64% …
author: Zhao, Xueqing
date published: 2002-05-23
date modified: 2026-07-24T02:51:30Z
provider: Ludwig Maxmilians Universität München
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Ludwig-Maximilians-Universität