Dérivés alkylés et arylés de l'acide nipécotique: synthèse et appréciation de l'activité inhibitrice de la capture du GABA en fonction de paramètres conformationnels et de biodisponibilité

Lapuyade, Gérard; Schlewer, Gilbert; N'Goka, Victor; Vernières, Jean-Claude; Chambón, J. P.; Lagrange, Jeanine; Lagrange, Philippe; Wermuth, Camille G.

doi:10.1016/0223-5234(87)90025-0

Cited by 9 publications

(9 citation statements)

References 9 publications

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“…[33] Flash column chromatography was performed on silica gel 60 (grading 0.035-0.070 mm, purchased from Merck and Acros). NMR spectroscopy was performed on a Bruker Avance III HD BioSpin ( 1 HNMR:4 00 or 500 MHz, 13 pure building blocks, and reaction progress was monitored by NMR.…”

Section: Methodsmentioning

confidence: 99%

“…synthesized 5‐substituted arecoline derivatives as well as the N ‐methylguvacine derivative 8 . Lapuyade et al . prepared nipecotic acid ( 6 ) derivatives substituted at positions 2, 3, 4, 5, or 6 with a methyl or phenyl residue (e.g., compound 9 ) and tested their inhibitory potencies of GABA transport in synaptosomes.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10] Besides theseN -substituted GABA uptake inhibitors, analogues showing various substitution patterns at the cyclic amino acids were also synthesized andt ested for their biological activity towardG AT1( Figure 2). 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%

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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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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2019

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“…4,4-Diphenylbutanal was prepared by starting from cyclopropyldiphenylmethanol (34). The action of hydrobromic acid upon this alcohol gave unsaturated bromide 35. Catalytic hydrogenation in the presence of palladium on charcoal gave 4,4-diphenyl-l-bromobutane (36), which was oxidized to aldehyde 37 via a Kornblum modified reaction.59 The expected aldehyde was accompanied by 22% of the corresponding alcohol 38. This side product could also be oxidized into the expected aldehyde via a Swern reaction60 (Scheme III).…”

Section: Synthesismentioning

confidence: 99%

“…X-ray analyses, as well as NMR studies, demonstrated that the carboxylic function of (-)-(fl)-nipecotic acid stayed in an equatorial position. 36 In such an orientation, the acidic group is coplanar with the mean plane of the molecule.…”

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confidence: 99%

GABA-uptake inhibitors: construction of a general pharmacophore model and successful prediction of a new representative

N'Goka¹,

Schlewer²,

Linget³

et al. 1991

J. Med. Chem.

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A model for the pharmacophore of GABA-uptake inhibitors was established using published structure-activity data and molecular modeling. The model accounted for the activities of different classes of GABA-uptake inhibitors. Analogues of guvacine substituted at position 6 were synthesized in order to confirm the model. 6-(3,3-Di-phenylpropyl)guvacine (30f), which fit well with the pharmacophore, had an in vitro IC50 of 0.1 microM. This value is as good as those of the best GABA-uptake inhibitors known today.

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Asymmetric Synthesis of δ‐Chloro‐β‐amino‐N‐sulfinyl Imidates as Versatile Chiral Building Blocks for the Synthesis of 2,3‐Disubstituted Piperidines

et al. 2015

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Mannich‐type reactions of chiral δ‐chloro‐N‐tert‐butanesulfinyl‐substituted imidates across N‐sulfonyl aldimines resulted in the efficient and anti‐stereoselective synthesis of new β‐(sulfonylamino)‐N‐sulfinyl imidates (dr > 99:1). These compounds were then successfully cyclized to give 2‐aryl‐N‐sulfonylpiperidine‐3‐(N‐sulfinyl)carbimidates in high yields. These proved to be useful intermediates for the synthesis of chiral methyl 2‐arylpiperidine‐3‐carboxylates as well as cis‐3‐amino‐2‐aryl‐N‐sulfonylpiperidines.

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Dérivés alkylés et arylés de l'acide nipécotique: synthèse et appréciation de l'activité inhibitrice de la capture du GABA en fonction de paramètres conformationnels et de biodisponibilité

Cited by 9 publications

References 9 publications

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

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

GABA-uptake inhibitors: construction of a general pharmacophore model and successful prediction of a new representative

Asymmetric Synthesis of δ‐Chloro‐β‐amino‐N‐sulfinyl Imidates as Versatile Chiral Building Blocks for the Synthesis of 2,3‐Disubstituted Piperidines

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