Molecular docking and structure-activity relationship studies on benzothiazole based non-peptidic BACE-1 inhibitors.

A similarity search on the structural analogs of an inhibitor of BACE-1 with IC(50) 2.8μM, which contained a P1 benzothiazole group together with a triazine ring linked by a secondary amine group, was described in this Letter and some more potent inhibitors against BACE-1 were identified. The most potent compound 5 (IC(50)=0.12μM) increases the inhibitory potency by 24 folds. Our results suggest that a pyrrolidinyl side group at the P3' and P4' of the inhibitors are favored for strong inhibition and a small aromatic group at the P4 position is also essential to the potency.