Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

Abstract

We report the synthesis of two series of compounds with 3,5-difluoromandelyl-alanyl or 3,5-difluorophenylacetyl-alanyl backbones coupled to various heterocyclic or peptidic moieties. These two series of compounds were evaluated for their inhibitory properties on β-secretase (BACE-1) enzymatic assay, a target enzyme for Alzheimer’s disease (AD) pathology. We found that both diastereomers obtained from the racemic mixture 7 of the coumarin derivative bearing a mandelyl moiety were the most potent BACE-1 inhibitors studied in this work (IC50 = 1 × 10−6 M). Analysis of the obtained results led to the hypothesis that introduction of a difluoromandelyl residue in place of a difluorophenylacetyl moiety may induce β-secretase inhibitory activity.

A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives

“…For example, hydroxy DAPT derivative 17 has been shown as a potent BACE-1 inhibitor, which initiates the production of amyloidogenic Aβ peptide, the principle component in plaque in AD patients 45. Our catalytic, asymmetric method allows the facile production of the chiral α-hydroxyl group which is responsible for a 10-fold increase in activity for 17 versus DAPT (Scheme 9).…”

Radical Arylation of Phenols, Phenyl Ethers, and Furans

“…Aminobenzocoumarin 33 has been reported as a substructure of the b-secretase (BACE-1) inhibitor 34 (Scheme 10). [45] b-Secretase represents a target enzyme for the treatment of Alzheimers disease. By using a radical biaryl coupling, fragment 33 is now conveniently accessible in three steps from methyl anthranilate (35) and 4-aminophenol (36).…”

Identification of Privileged Scaffolds from a Diversified Chemical Library forβ-Secretase Inhibition

“…Twenty compounds showed such IC 50 values and more precisely, five of them were in the range of 10 µM. Some of these compounds have yet been described [26].…”