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Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors
journal contribution
posted on 2019-11-14, 15:47 authored by Tommi
P. Kilpeläinen, Jonna K. Tyni, Maija K. Lahtela-Kakkonen, Tony S. Eteläinen, Timo T. Myöhänen, Erik A. A. Wallén4-Phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines
were studied as prolyl oligopeptidase inhibitors. The compounds were
more potent than expected from the assumption that the tetrazole would
also here be a bioisostere of the carboxylic acid group and the corresponding
carboxylic acids are at their best only weak inhibitors. The aminoacyl
groups l-prolyl and l-alanyl gave potent inhibitors
with IC50 values of 12 and 129 nM, respectively. This was
in line with typical prolyl oligopeptidase inhibitors; however, we
did observe a difference with N-methyl-l-alanyl, which gave potent inhibitors in typical prolyl oligopeptidase
inhibitors but not in our novel compound series. Furthermore, all
studied 4-phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines
decreased α-synuclein dimerization at the concentration of 10
μM, also when they were only weak inhibitors of the proteolytic
activity of the enzyme with an IC50 value of 205 μM.
Molecular docking studies revealed that the compounds are likely to
bind differently to the enzyme compared to typical prolyl oligopeptidase
inhibitors represented in this study by 4-phenylbutanoyl-aminoacyl-2(S)-cyanopyrrolidines.