Synthesis and GABA uptake inhibitory properties of 6-aryl iminoxymethyl substituted nipecotic acids

N'Goka, Victor; Stenbøl, Tine B.; Krogsgaard‐Larsen, Povl; Schlewer, Gilbert

doi:10.1016/j.ejmech.2004.07.003

Cited by 13 publications

(8 citation statements)

References 15 publications

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“…1 H NMR (400 MHz, C 2 Cl 4 D 2 , 80 °C): δ 1.44 (s, 9 H), 2.58 (dd, J = 16.9/ 6.0 Hz, 1 H), 2.70 (dd, J = 16.9/7.3 Hz, 1 H), 3.03 (quin, J = 6. 28 According to GP3 with rac-35 (86 mg, 0.30 mmol), tert-butyl carbazate (66 mg, 0.49 mmol), AcOH (0.043 mL, 0.75 mmol) and NaBH 3 CN (81 mg, 1.2 mmol, added in three portions). rac-37 was obtained as a colorless oil (90 mg; 74%).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…All these selective and potent GAT1 inhibitors possess a hydrophilic amino acid “head” and a lipophilic aromatic moiety that is connected to the amino acid via a spacer originating from the amino nitrogen of the amino acid. There have been extensive efforts − to develop analogous GAT1 inhibitors with a different substitution pattern of the cyclic amino acid. For example, 4-substituted nipecotic acid derivatives including compound rac - 8 and 6-substituted guvacine derivatives including compound 9 were synthesized and tested for their inhibitory potencies of the GABA transport.…”

Section: Introductionmentioning

confidence: 99%

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Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

et al. 2018

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This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5- instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compounds and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured rac-16gf bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake experiments revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid derivative up to now. Therefore, the herein introduced 5-substituted nipecotic acid derivatives could serve as valuable tools for investigations of allosterically modulated GABA transport mediated by GAT1 and furthermore as starting point for a new class of GAT1 inhibitors.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

et al. 2018

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“…Furthermore, Hoesl et al . and N′Goka et al . synthesized 6‐substituted nipecotic acid ( 6 ) derivatives (e.g., compound 11 ).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, Müller-Uri et al [12] synthesized 5-substituteda recoline derivatives as well as the N-methylguvacine derivative 8.L apuyade et al [13] prepared nipecotic acid (6)d erivatives substituted at positions 2, 3, 4, 5, or 6w ith am ethyl or phenylr esidue (e.g.,c ompound 9)a nd tested their inhibitory potencieso fG ABA transport in synaptosomes. N'Goka et al [14] synthesized 6-substitutedg uvacine (7)d erivatives of which compound 10 showedi nvitro inhibitory potency of GABA uptake similar to those of compounds 2-4.F urthermore, Hoesl et al [15] and N'Goka et al [16,17] synthesized 6-substituted nipecotic acid (6)d erivatives (e.g., compound 11).…”

Section: Introductionmentioning

confidence: 99%

MS‐Based Screening of 5‐Substituted Nipecotic Acid Derived Hydrazone Libraries as Ligands of the GABA Transporter 1

2019

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A screening of compound libraries based on nipecotic acid derivatives with lipophilic residues attached to the scarcely explored 5‐position of the core structure was used for the search of new inhibitors of the γ‐aminobutyric acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With nipecotic acid derived hydrazone rac‐16 h [rac‐(3R,5S)‐{5‐[(E)‐2‐{[5‐(2‐phenylethynyl)thiophen‐2‐yl]methylidene}hydrazin‐1‐yl]piperidine‐3‐carboxylic acid}‐sodium chloride (1/2)], one hit was found and evaluated displaying sub‐micromolar potency (pKi=6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5‐(2‐phenylethynyl)thiophen‐2‐yl residue attached to the 5‐position of nipecotic acid via a three‐atom spacer, compound rac‐16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5‐substituted nipecotic acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1‐mediated GABA transport.

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“…From the triarylethenebased extended p-system library, we were able to find a number of interesting fluorescent materials as well as interesting photophysical properties. 1,2 During these investigations targeting multisubstituted olefins, we became aware that pharmaceutically important 1,1-diaryl-1-alkenes 3 (Figure 1) 8,9 would be obtained straightforwardly if an efficient cross-coupling reaction of b,b-diarylvinylboronate esters 2 with alkyl halides could be developed (Scheme 2). Herein we describe an efficient and straightforward synthesis of 1,1-diaryl-1-alkenes 3 using vinylboronate ester 1 as a platform.…”

mentioning

confidence: 99%

Versatile Synthesis of 1,1-Diaryl-1-alkenes Using Vinylboronate Ester as a Platform

Tonogaki¹,

Soga²,

Itami³

et al. 2005

Synlett

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A sequence of double Mizoroki-Heck reaction of vinylboronate pinacol ester with aryl halides followed by Suzuki-Miyaura coupling of thus-generated b,b-diarylvinylboronate esters with alkyl halides produces pharmaceutically important 1,1-diaryl-1-alkenes very efficiently. In the Pd-catalyzed Suzuki-Miyaura coupling step, the use of bulky electron-rich ligands such as P(t-Bu) 2 Me and PCy 2 (t-Bu) were found to be very effective.

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Synthesis and GABA uptake inhibitory properties of 6-aryl iminoxymethyl substituted nipecotic acids

Cited by 13 publications

References 15 publications

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

MS‐Based Screening of 5‐Substituted Nipecotic Acid Derived Hydrazone Libraries as Ligands of the GABA Transporter 1

Versatile Synthesis of 1,1-Diaryl-1-alkenes Using Vinylboronate Ester as a Platform

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