Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors.,ACS Medicinal Chemistry Letters

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Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-11-11 , DOI: 10.1021/acsmedchemlett.9b00394
Tommi P Kilpeläinen ₁ , Jonna K Tyni ₂ , Maija K Lahtela-Kakkonen ₂ , Tony S Eteläinen ₁ , Timo T Myöhänen ₁ , Erik A A Wallén ₃

Affiliation

4-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.

中文翻译：

四唑作为特征性脯氨酰寡肽酶抑制剂中亲电子基团的替代物。

研究了4-苯基丁酰基-氨基酰基-2（S）-四唑基吡咯烷酮作为脯氨酰寡肽酶抑制剂。从四唑也将是羧酸基团的生物等排体并且相应的羧酸在其最佳状态下仅是弱抑制剂的假设出发，这些化合物比预期的更有效。氨酰基1-脯氨酰基和1-丙氨酰基产生了有效的抑制剂，IC50值分别为12和129 nM。这与典型的脯氨酰寡肽酶抑制剂是一致的。但是，我们确实观察到了与N-甲基-1-丙氨酰的区别，后者在典型的脯氨酰寡肽酶抑制剂中提供了有效的抑制剂，但在我们的新型化合物系列中却没有。此外，所有研究的4-苯基丁酰基-氨基酰基-2（S）-四唑基吡咯烷酮在10μM的浓度下均会降低α-突触核蛋白的二聚作用，当它们只是酶的蛋白水解活性的弱抑制剂时，IC50值为205μM。分子对接研究表明，与本研究中以4-苯基丁酰基-氨基酰基-2（S）-氰基吡咯烷酮为代表的典型脯氨酰寡肽酶抑制剂相比，该化合物与酶的结合方式可能不同。

更新日期：2019-11-14

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