Development of Kinase Inactive PD173955 Analogues for Reducing Production of Aβ Peptides

Compound 3a, DV2-103, is a kinase inactive analogue
of a potent Abl1/Src kinase inhibitor, PD173955, 2. Both
compounds, 2 and 3a, are known to reduce
production of beta amyloid (Aβ) peptide in cells and animal
models. We have now prepared and evaluated a series of PD-173955 analogues,
several of which reduced Aβ production potently. This occurs
in cells expressing human full-length amyloid precursor protein (APP)
and not in cells expressing APP β-C terminal fragment (APP-C99),
suggesting that the kinase inactive analogues strongly affect β-secretase
(BACE1) cleavage of APP, similarly to Gleevec. A combination of the
kinase inactive analogues of PD173955 with a BACE1 inhibitor (BACEi),
namely, BACE IV, strongly reduced Aβ levels in cells, as noted
previously with Gleevec and analogues. Several potent compounds also
penetrated and accumulated in mouse brain in high nanomolar to low
micromolar concentration.