A new class of conformationally rigid analogues of 4-amino-5-halopentanoic acids, potent inactivators of gamma-aminobutyric acid aminotransferase.

@article{Qiu2000ANC,
  title={A new class of conformationally rigid analogues of 4-amino-5-halopentanoic acids, potent inactivators of gamma-aminobutyric acid aminotransferase.},
  author={J. Qiu and R. Silverman},
  journal={Journal of medicinal chemistry},
  year={2000},
  volume={43 4},
  pages={
          706-20
        }
}
Recently, we found (Qiu, J.; Pingsterhaus, J. M.; Silverman, R. B. J. Med. Chem. 1999, 42, 4725-4728) that conformationally rigid analogues of the GABA aminotransferase (GABA-AT) inactivator vigabatrin were not inactivators of GABA-AT. To determine if this is a general phenomenon of GABA-AT inactivators, several mono- and di-halogen-substituted conformationally rigid analogues (7-15) of other GABA-AT inactivators, 4-amino-5-halopentanoic acids, were synthesized as potential inactivators of GABA… Expand
New substrates and inhibitors of gamma-aminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group: design, synthesis, and biological activity.
TLDR
The synthesized compound 8 showed time-dependent inhibition of GABA-AT, but its potency is lower than that of vigabatrin, suggesting that the tetrazole ring, the carboxylate bioisostere, exists in its deprotonated form in the enzyme active site. Expand
Structural modifications of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid, a potent irreversible inhibitor of GABA aminotransferase.
TLDR
The tetrazole isostere of 2 of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid has been found to be a time-dependent inactivator of GABA aminotransferase, and 4 is the most lipophilic of the three, indicating potential for improved bioavailability. Expand
(+/-)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic acid. A potent GABA aminotransferase inactivator that irreversibly inhibits via an elimination-aromatization pathway.
Inhibition of gamma-aminobutyric acid aminotransferase (GABA-AT) increases the concentration of GABA, an inhibitory neurotransmitter in human brain, which could have therapeutic applications for aExpand
Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase.
TLDR
An integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry was established to facilitate the design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue, 25-times more efficient as an inactivator of GABA-AT. Expand
Enantiomers of 4-amino-3-fluorobutanoic acid as substrates for gamma-aminobutyric acid aminotransferase. Conformational probes for GABA binding.
TLDR
The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily determined by other biophysical approaches. Expand
A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid.
TLDR
This work rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective hOAT time-dependent inhibitors, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Expand
The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors.
TLDR
It is shown that thecyclopentane and cyclopentene analogues of GABA affect GABA(C) receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABA( C) receptors. Expand
Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors.
TLDR
On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect. Expand
Syntheses and evaluation of fluorinated conformationally restricted analogues of GABA as potential inhibitors of GABA aminotransferase.
TLDR
Four fluorine-containing analogues of GABA with conformations restricted by a cyclohexane ring system were designed and synthesized, but unlike some of their five-membered ring counterparts, minimal inhibition of GABA-AT was observed, likely due to the rigid chair conformation of these compounds. Expand
Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase.
TLDR
The synthesis and evaluation of a series of heteroaromatic GABA analogues as substrates of GABA-AT are reported, which will be used as the basis for the design of novel enzyme inactivators. Expand
...
1
2
3
4
5
...