Modular synthesis of 2,4-diaminoanilines as CNS drug-like non-covalent inhibitors of asparagine endopeptidase

Lorenzo Calugi; Elena Lenci; Francesca Bianchini; Alessandro Contini; Andrea Trabocchi

doi:10.1016/j.bmc.2022.116746

Modular synthesis of 2,4-diaminoanilines as CNS drug-like non-covalent inhibitors of asparagine endopeptidase

Bioorg Med Chem. 2022 Jun 1:63:116746. doi: 10.1016/j.bmc.2022.116746. Epub 2022 Apr 12.

Authors

Lorenzo Calugi¹, Elena Lenci¹, Francesca Bianchini², Alessandro Contini³, Andrea Trabocchi⁴

Affiliations

¹ Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
² Department of Biomedical, Experimental and Clinical Sciences ''Mario Serio", University of Florence, Viale 8 Morgagni 50, I-50134 Florence, Italy.
³ Department of Pharmaceutical Sciences, University of Milan, Via Venezian 21, I-20133 Milan, Italy.
⁴ Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: andrea.trabocchi@unifi.it.

PMID: 35430537
DOI: 10.1016/j.bmc.2022.116746

Abstract

Asparagine endopeptidase (AEP), also called legumain, is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Recent studies showed that it possesses δ-secretase activity and that it is implicated in numerous neurological diseases such as Alzheimer's disease (AD). Following evidence of aryl-morpholines as useful asparagine endopeptidase inhibitors, a series of morpholinoanilines with diverse substituents at ortho position were synthesized in view of improving the potency and scope of this molecular scaffold, allowing to identify ethyl 2-isonipecotate-4-morpholinoaniline possessing inhibition potency in the nanomolar range. CNS MPO (CNS MultiParameter Optimization) calculations revealed that most of the compounds developed in this work show physicochemical parameters in the desirable range for CNS drug candidates.

Keywords: Anilines; Cysteine protease; Delta-secretase; Drug discovery; Enzyme.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Central Nervous System Agents / therapeutic use
Cysteine Endopeptidases* / chemistry
Humans
Protease Inhibitors / pharmacology
Protease Inhibitors / therapeutic use

Substances

Central Nervous System Agents
Protease Inhibitors
Cysteine Endopeptidases
asparaginylendopeptidase