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.
Lorenzo Calugi  1 ,  Elena Lenci  1 ,  Francesca Bianchini  2 ,  Alessandro Contini  3 ,  Andrea Trabocchi  4
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: [email protected].
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.
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