Facile synthesis of the glucosylceramide synthase inhibitor GZ667161

Abstract GZ667161 (GZ-161) is a quinuclidine-based small molecule inhibitor of the lysosomal enzyme glucosylceramide synthase. It represents an important tool molecule for studying the contribution of glycosphingolipids to disease pathology in lysosomal storage disorders such as Gaucher disease and GBA1 Parkinson’s disease. GZ667161 is not commercially available. The published synthesis involves 6 steps and proceeds in 18% overall reported yield. As part of a drug discovery program targeting Type 2 Gaucher disease we required quantities of GZ667161 that would support animal studies. To facilitate the project, we devised and executed an efficient 4-step convergent synthesis of the compound.