Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors

Hellenbrand, Tim; Höfner, Georg; Wein, Thomas; Wanner, Klaus T.

doi:10.1016/j.bmc.2016.03.038

Cited by 18 publications

(28 citation statements)

References 28 publications

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“…Notably, the binding affinity of rac ‐ 16 h is similar to that of hydrazone rac ‐ 13 (p K i =6.67±0.03), which was found to be the most potent compound in our recently described screening campaign, and compared with tiagabine ( 2 ; p K i =7.56±0.06) as an example of an established potent GAT1 inhibitor, the nominal difference of the p K i values is less than one log unit. Furthermore, the binding affinity of 5‐substituted nipecotic acid derived hydrazone rac ‐ 16 h , like that of rac ‐ 13 , is distinctly higher than those of known 4‐substituted nipecotic acid derivatives such as compound rac ‐ 12 (p K i =4.85) . This implies that the 5‐position represents a more favored substitution pattern than the 4‐position, leading to potent ligands of GAT1.…”

Section: Resultsmentioning

confidence: 95%

“…However, such conclusions require further examinations, because for 4‐substituted nipecotic acid derivatives, only a limited range of aromatic residues attached to the hydrophilic moiety via a spacer have been explored so far (e.g., biphen‐2‐yl or 2‐benzylphenyl residues as described in Ref. ). In contrast, the generation of pseudostatic hydrazone libraries so far only applied for 1‐ and 5‐substituted nipecotic acid derivatives is to be considered a powerful tool in drug research, allowing screening for a vast diversity of aromatic residues (as described herein and previously) .…”

Section: Resultsmentioning

confidence: 99%

“…Based on molecular modeling the unsubstituted ( R )‐nipecotic acid [( R )‐ 6 ] preferably adopts a binding pose in which the piperidine nitrogen atom faces the intracellular side, whereas for the larger inhibitor tiagabine ( 2 ) the binding pose of the piperidine ring is switched with the nitrogen and the attached arylalkyl residue facing the extracellular side of the transporter . On the basis of these results, we concluded that substitutions particularly at positions 4 or 5 with an appropriate spacer and lipophilic residue could yield GABA uptake inhibitors in which the binding pose of the piperidine ring is retained relative to that of unsubstituted ( R )‐ 6 . It is hoped that such compounds could bring new insight into the interactions between the ligand and target molecules or could even lead to novel GABA uptake inhibitors with higher potencies.…”

Section: Introductionmentioning

confidence: 96%

“…It is hoped that such compounds could bring new insight into the interactions between the ligand and target molecules or could even lead to novel GABA uptake inhibitors with higher potencies. Initial experiments exploiting nipecotic acid ( 6 ) and N ‐methylnipecotic acid derivatives substituted at the 4‐position (e.g., compound rac ‐ 12 ) did not yet reveal any new GABA uptake inhibitors with striking activity . However, more recently, we reported an approach that led to 5‐substitituted nipecotic acid derivatives with interesting biological activities.…”

Section: Introductionmentioning

confidence: 98%

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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: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

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

2019

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“…General procedure for ester hydrolysis with Ba(OH) 2 ( GP6 ) : The ester (1 equiv) was dissolved in EtOH/H 2 O (2:1) and Ba(OH) 2 ⋅8 H 2 O (2 equiv) was added. The suspension was then stirred at RT.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3‐Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1

2019

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A new class of nipecotic acid and guvacine derivatives has been synthesized and characterized for their inhibitory potency at mGAT1–4 and binding affinity for mGAT1. Compounds of the described class are defined by a four‐carbon‐atom allenyl spacer connecting the nitrogen atom of the nipecotic acid or guvacine head with an aromatic residue. Among the compounds investigated, the mixture of nipecotic acid derivatives rac‐{(Ra)‐1‐[4‐([1,1′:2′,1′′‐terphenyl]‐2‐yl)buta‐2,3‐dien‐1‐yl](3R)‐piperidine‐3‐carboxylic acid} and rac‐{(Sa)‐1‐[4‐([1,1′:2′,1′′‐terphenyl]‐2‐yl)buta‐2,3‐dien‐1‐yl](3R)‐piperidine‐3‐carboxylic acid} (21 p), possessing an o‐terphenyl residue, was identified as highly selective and the most potent mGAT1 inhibitor in this study. For the (R)‐nipecotic acid derived form of 21 p, the inhibitory potency in [3H]GABA uptake assays was determined as pIC50=6.78±0.08, and the binding affinity in MS Binding Assays as pKi=7.10±0.12. The synthesis of the designed compounds was carried out by a two‐step procedure, generating the allene moiety via allenylation of terminal alkynes which allows broad variation of the terminal phenyl and biphenyl subunit.

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Identification of Pyrrolidine‐3‐acetic Acid Derived Oximes as Potent Inhibitors of γ‐Aminobutyric Acid Transporter 1 through Library Screening with MS Binding Assays

2018

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In this study, pyrrolidine‐3‐acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ‐aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine‐3‐acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine‐3‐acetic acid motif were found, of which the most potent oxime, possessing a 2′,4′‐dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi=7.87±0.01).

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Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors

Cited by 18 publications

References 28 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

Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3‐Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1

Identification of Pyrrolidine‐3‐acetic Acid Derived Oximes as Potent Inhibitors of γ‐Aminobutyric Acid Transporter 1 through Library Screening with MS Binding Assays

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