Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α-Synuclein Mouse Models of Parkinson's Disease

被引：7

作者：

Kilpelainen, Tommi P. ^{[1
]}

Patsi, Henri T. ^{[2
]}

Svarcbahs, Reinis ^{[1
]}

Julku, Ulrika H. ^{[1
]}

Etelainen, Tony S. ^{[1
]}

Cui, Hengjing ^{[1
,3
]}

Auno, Samuli ^{[1
]}

Sipari, Nina ^{[4
]}

Norrbacka, Susanna ^{[1
]}

Leino, Teppo O. ^{[2
]}

Jantti, Maria ^{[1
]}

Myohanen, Timo T. ^{[1
,3
]}

Wallen, Erik A. A. ^{[2
]}

机构：

[1] Univ Helsinki, Div Pharmacol & Pharmacotherapy, Helsinki 00014, Finland

[2] Univ Helsinki, Fac Pharm, Drug Res Program, Div Pharmaceut Chem & Technol, Helsinki 00014, Finland

[3] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland

[4] Univ Helsinki, Dept Biosci, Viikki Metabol Unit, Helsinki 00014, Finland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 11期

基金：

芬兰科学院;

关键词：

ENDOPEPTIDASE INHIBITOR; EFFICIENT SYNTHESIS; OVEREXPRESSION; AUTOPHAGY; KYP-2047; DRUG; PHARMACOKINETICS; PHOSPHORYLATION; AGGREGATION; ACTIVATION;

D O I：

10.1021/acs.jmedchem.3c00235

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Prolyl oligopeptidase (PREP) is a widely distributedserine proteasein the human body cleaving proline-containing peptides; however, recentstudies suggest that its effects on pathogenic processes underlyingneurodegeneration are derived from direct protein-protein interactions(PPIs) and not from its regulation of certain neuropeptide levels.We discovered novel nonpeptidic oxazole-based PREP inhibitors, whichdeviate from the known structure-activity relationship forPREP inhibitors. These new compounds are effective modulators of thePPIs of PREP, reducing alpha-synuclein (alpha Syn) dimerizationand enhancing protein phosphatase 2A activity in a concentration-responsemanner, as well as reducing reactive oxygen species production. Fromthe best performing oxazoles, HUP-55 was selected for in vivo studies. Its brain penetration was evaluated, andit was tested in alpha Syn virus vector-based and alpha Syn transgenicmouse models of Parkinson's disease, where it restored motorimpairment and reduced levels of oligomerized alpha Syn in the striatumand substantia nigra.

引用

页码：7475 / 7496

页数：22

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