Discovery And X-Ray Crystallographic Analysis Of A Spiropiperidine Iminohydantoin Inhibitor Of Beta-Secretase

A high-throughput screen at 100.mu M inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.