Thiophene substituted acylguanidines as BACE1 inhibitors

A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE I and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay. (C) 2007 Elsevier Ltd. All rights reserved.