The aspartic protease BACE-1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer’s disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase therefore inhibiting BACE-1 and preventing the abnormal generation of Aβ is a rational approach to preventing progression of AD. Thus, many research efforts are focusing at the identification of new BACE-1 inhibitors as drug candidates. Generally, BACE-1 inhibitors are grouped into two families: substrate-based inhibitors designed as peptidomimetic inhibitors and nonpeptidomimetic ones. The research on non-peptidomimetic small-sized BACE-1 inhibitors remains the most interesting approach since these compounds hold an improved bioavailability after systemic administration due to good blood-brain barrier permeability in comparison to peptidomimetic inhibitors. Our research group discovered a new potent and selective BACE-1 inhibitors, a series of novel heterocyclic compounds related to Lipocrine were designed and synthesised. Lipocrine is the first compound that inhibits the catalytic activity of AChE and AChE-induced amyloid-β aggregation and protects against reactive oxygen species (1). Lipocrine is considered as a promising lead compound for the treatment of Alzheimer’s disease hence it was evaluated for inhibition of BACE-1 and exhibited BACE-1 IC50 in nanomolar range (IC50 = 58 nM). Thus, it was used as a lead compound for the design and synthesis of new ligands bearing new heterocyclic rather than the tetrahydroacridinic moiety. Moreover, dithiolane moiety was found to be optimal for activity since the tiophene analogue lacks affinity for BACE-1. Modifications of the tetrahydroacridinic moiety with 2-subsituted-6,7-dimethoxyquinazoline residue provided the compounds 2 that exhibited an enhanced activity. Thus, in order to establish structure-activity relationships for BACE-1 inhibition, different modifications were carried out in the prototype 2. The substitution of the 2-Chloro-6,7-dimethoxyquinazolinic residue with 7-Chloro-quinoline-2,3-dicarboxylic acid dimethyl ester provided a less potent compound 3 (IC50= 490 nM). The replacement of 2-Cl with alternative substituent like -H, -CH3, -NH2, -CN gave some 2-substituted 6,7-dimethoxyquinazolinic compounds to be evaluated as novel BACE-1 inhibitors.

New quinazoline compounds as non-peptidomimetic BACE-1 inhibitors in the treatment of Alzheimer's disease

MATERA, RICCARDO;MINARINI, ANNA;ROSINI, MICHELA;ANDRISANO, VINCENZA;MANCINI, FRANCESCO;MELCHIORRE, CARLO
2007

Abstract

The aspartic protease BACE-1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer’s disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase therefore inhibiting BACE-1 and preventing the abnormal generation of Aβ is a rational approach to preventing progression of AD. Thus, many research efforts are focusing at the identification of new BACE-1 inhibitors as drug candidates. Generally, BACE-1 inhibitors are grouped into two families: substrate-based inhibitors designed as peptidomimetic inhibitors and nonpeptidomimetic ones. The research on non-peptidomimetic small-sized BACE-1 inhibitors remains the most interesting approach since these compounds hold an improved bioavailability after systemic administration due to good blood-brain barrier permeability in comparison to peptidomimetic inhibitors. Our research group discovered a new potent and selective BACE-1 inhibitors, a series of novel heterocyclic compounds related to Lipocrine were designed and synthesised. Lipocrine is the first compound that inhibits the catalytic activity of AChE and AChE-induced amyloid-β aggregation and protects against reactive oxygen species (1). Lipocrine is considered as a promising lead compound for the treatment of Alzheimer’s disease hence it was evaluated for inhibition of BACE-1 and exhibited BACE-1 IC50 in nanomolar range (IC50 = 58 nM). Thus, it was used as a lead compound for the design and synthesis of new ligands bearing new heterocyclic rather than the tetrahydroacridinic moiety. Moreover, dithiolane moiety was found to be optimal for activity since the tiophene analogue lacks affinity for BACE-1. Modifications of the tetrahydroacridinic moiety with 2-subsituted-6,7-dimethoxyquinazoline residue provided the compounds 2 that exhibited an enhanced activity. Thus, in order to establish structure-activity relationships for BACE-1 inhibition, different modifications were carried out in the prototype 2. The substitution of the 2-Chloro-6,7-dimethoxyquinazolinic residue with 7-Chloro-quinoline-2,3-dicarboxylic acid dimethyl ester provided a less potent compound 3 (IC50= 490 nM). The replacement of 2-Cl with alternative substituent like -H, -CH3, -NH2, -CN gave some 2-substituted 6,7-dimethoxyquinazolinic compounds to be evaluated as novel BACE-1 inhibitors.
Programme and abstracts 16th Camerino-Noordwijkrhout symposium "An overview of receptor chemistry"
115
115
Matera R; Minarini A; Rosini M; Andrisano V; Mancini F; Melchiorre C.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/47555
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