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

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 Aβ40 in transgenic mice with a single subcutaneous dose.

Graphical abstractDesign and optimization of a novel series of piperazine sulfonamide inhibitors of BACE1 are described, with an emphasis on SAR of the non-prime side and S2′ binding motifs. The lead inhibitor demonstrated a prolonged inhibition of peripheral Aβ40 in transgenic mice with a single acute dose.Figure optionsDownload full-size imageDownload as PowerPoint slide