Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization

Abstract

With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2′ sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Aβ 40 in transgenic mice with a single subcutaneous dose.