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.

Modular synthesis of 2,4-diaminoanilines as CNS drug-like non-covalent inhibitors of asparagine endopeptidase / Calugi L.; Lenci E.; Bianchini F.; Contini A.; Trabocchi A.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - ELETTRONICO. - 63:(2022), pp. 116746-116746. [10.1016/j.bmc.2022.116746]

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

Calugi L.;Lenci E.;Bianchini F.;Trabocchi A.
2022

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.
63
116746
116746
Goal 3: Good health and well-being
Calugi L.; Lenci E.; Bianchini F.; Contini A.; Trabocchi A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1265919
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