Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands

Abstract

We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among AMPA receptor subtypes, confirmed also by an unusual binding mode observed on the crystal structures in complex with the AMPA receptor GluA2 agonist binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist binding sites of the NMDA receptor. These observations demonstrate novel features that arise when employing a hydroxyl-triazole moiety as bioisostere for the distal carboxylic acid in glutamate receptor agonists.

Ionotropic Glutamate Receptor GluA2 in Complex with Bicyclic Pyrimidinedione-Based Compounds: When Small Compound Modifications Have Distinct Effects on Binding Interactions

“…34 Proteins Preparation. The 3D-structure of the GluA2-LBD was retrieved from PDB (PDB code 6Q54), 35 while the GluA2-LBD in complex with 7 was obtained by the presented structure. The structures were imported into the Schrodinger Maestro molecular modeling environment.…”

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

“…Pippione et al have reported two C 5 -substituted 4-hydroxy-1,2,3-triazole 2-amino-3-(3hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) analogs as antagonists of the AMPA receptor. is sca old has the opportunity to regio-direct substituents in two di erent directions, reaching additional binding areas of the receptor to improve properties such as potency and selectivity, compared to one in the isoxazolyl moiety in AMPA [142,143]. Also, the N 1 -and N 2 -substituted 4-hydroxy-1,2,3-triazole moieties act as a carboxylic acid bioisostere.…”

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

“…The reaction with 4-methoxybenzyl bromide afforded a mixture of the regioisomers 19a and 19b at a ratio of 61% and 27%, respectively. The mixture was resolved by flash chromatography, and the structure characterization of each isomer was attributed using the benzylic 13 C chemical shift (70.7 and 43.2 for ArCH 2 O and ArCH 2 N, respectively) according to a previous 2D NMR spectra analysis reported by Sainas et al, 2018, and 13 C chemical shift analysis of other oxygen vs nitrogen alkylated compounds. − Ester 19a was then hydrolyzed under basic conditions to obtain the corresponding acid 20 (quantitative yield), which was then used for the preparation of the common intermediate 21 . Starting from acid 20 , the corresponding acyl chloride was obtained via treatment with oxalyl chloride and was used without any further purification in the reaction with the dimethylaluminum amide of 2,3,5,6-tetrafluoro-4-bromoaniline, giving the desired amide 21 in a 55% yield.…”

“…1 H NMR (600 MHz, chloroform-d 3 ) δ 1.39 (t, 3H, J = 7.1 Hz, -OCH 2 CH 3 ), 1.58 (s, 9H, -OC(CH 3 ) 3 ), 4.36 (q, 2H, J = 7.0 Hz, -OCH 2 CH 3 ), 6.96 (t, 1H, J = 6.8 Hz, H-b), 7.42 (t, 1H, J = 7.9 Hz, H-c), 8.08 (d, 1H, J = 8.8 Hz, H-d), 8.38 (d, 1H, J = 6.6 Hz, H-a). Ethyl 2-((tert-Butoxycarbonyl)oxy)-7-chloropyrazolo[1,5-a]pyridine-3-carboxylate (41). LiHMDS (1.0 M THF solution: 0.980 mL, 0.98 mmol, 1.5 equiv) was added dropwise to a solution of 40 (0.400 g, 0.654 mmol) in dry THF (10 mL) and cooled to −78 °C.…”