Another example—this time from my own history—of incremental improvement in drug discovery. In 1988 it was discovered in Oxford that deoxynojirimycin (DNM), an α‑glucosidase inhibitor found in… | Stan Van Boeckel

Another example—this time from my own history—of incremental improvement in drug discovery. In 1988 it was discovered in Oxford that deoxynojirimycin (DNM), an α‑glucosidase inhibitor found in mulberry leaves, inhibits HIV. At Organon I started a follow‑up program and we found that activity increased importantly with long N‑alkyl substituents on DNM. Unfortunately, those compounds were (cell)‑toxic due to strong amphiphilicity; however, inserting an oxygen atom into the long chain preserved activity while eliminating toxicity (a related molecule, UV‑4, recently reached Phase 1 as a broad‑spectrum antiviral). In Oxford they continued with shorter alkyl chains, which in 1994 laid the foundation for miglustat, approved in 2002 for lysosomal storage disorders through inhibition of GCS and GBA2. Overkleeft in Amsterdam returned in 1998 to the concept of a lipophilic side chain containing oxygen and created the more potent MZ21. Miglustat and MZ21, however, still inhibit α‑glucosidases in the GI tract, causing unpleasant side effects. The undesired α‑glucosidase activity could be minimized by giving the aza‑sugar the L‑Ido instead of the D‑Gluco configuration. Ultimately, the Overkleeft group and I (Leiden) combined all knowledge into nizubaglustat: highly (equi)potent on GCS and GBA2, CNS‑penetrant, and suitable for low once‑daily dosing. Nizubaglustat is now in Phase 3 clinical trials (NPC and Gangliosidosis by Azafaros) and will hopefully be approved before 2028—forty years after the first results with deoxynojirimycin (DNM).