2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors

Henri T Pätsi; Tommi P Kilpeläinen; Samuli Auno; Pyry M J Dillemuth; Khaled Arja; Maija K Lahtela-Kakkonen; Timo T Myöhänen; Erik A A Wallén

doi:10.1021/acsmedchemlett.1c00399

2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors

ACS Med Chem Lett. 2021 Sep 17;12(10):1578-1584. doi: 10.1021/acsmedchemlett.1c00399. eCollection 2021 Oct 14.

Authors

Henri T Pätsi¹, Tommi P Kilpeläinen², Samuli Auno², Pyry M J Dillemuth¹, Khaled Arja¹, Maija K Lahtela-Kakkonen³, Timo T Myöhänen^{2

3

4}, Erik A A Wallén¹

Affiliations

¹ Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
² Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
³ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
⁴ Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Kiinanmyllynkatu 10, 20014 Turku, Finland.

Abstract

Different five-membered nitrogen-containing heteroaromatics in the position of the typical electrophilic group in prolyl oligopeptidase (PREP) inhibitors were investigated and compared to tetrazole. The 2-imidazoles were highly potent inhibitors of the proteolytic activity. The binding mode for the basic imidazole was studied by molecular docking as it was expected to differ from the acidic tetrazole. A new putative noncovalent binding mode with an interaction to His680 was found for the 2-imidazoles. Inhibition of the proteolytic activity did not correlate with the modulating effect on protein-protein-interaction-derived functions of PREP (i.e., dimerization of alpha-synuclein and autophagy). Among the highly potent PREP inhibiting 2-imidazoles, only one was also a potent modulator of PREP-catalyzed alpha-synuclein dimerization, indicating that the linker length on the opposite side of the molecule from the five-membered heteroaromatic is critical for the disconnected structure-activity relationships.