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Development of Gleevec Analogues for Reducing Production of beta-Amyloid Peptides through Shifting beta-Cleavage of Amyloid Precursor Proteins
Imatinib mesylate, 1a, inhibits production of beta-amyloid (Abeta) peptides both in cells and in animal models. It reduces both the beta-secretase and gamma-secretase cleavages of the amyloid precursor protein (APP) and mediates a synergistic effect, when combined with a beta-secretase inhibitor, BACE IV. Toward developing more potent brain-permeable leads, we have synthesized and evaluated over 75 1a-analogues. Several compounds, including 2a-b and 3a-c, inhibited production of Abeta peptides with improved activity in cells. These compounds affected beta-secretase cleavage of APP similarly to 1a. Compound 2a significantly reduced production of the Abeta42 peptide, when administered (100 mg/kg, twice daily by oral gavage) to 5 months old female mice for 5 days. A combination of compound 2a with BACE IV also reduced Abeta levels in cells, more than the additive effect of the two compounds. These results open a new avenue for developing treatments for Alzheimer’s disease using 1a-analogues.
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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem