Hydroxypyridinethione Inhibitors of Human Insulin-Degrading Enzyme

Insulin-degrading enzyme (IDE) is a human mononuclear Zn2+-dependent metalloenzyme that is widely regarded as the primary peptidase responsible for insulin degradation. Despite its name, IDE is also critically involved in the hydrolysis of several other disparate peptide hormones, including glucagon, amylin, and the amyloid beta-protein. As such, the study of IDE inhibition is highly relevant to deciphering the role of IDE in conditions such as type-2 diabetes mellitus and Alzheimer disease. There have been few reported IDE inhibitors, and of these, inhibitors that directly target the active-site Zn2+ ion have yet to be fully explored. In an effort to discover new, zinc-targeting inhibitors of IDE, a library of similar to 350 metal-binding pharmacophores was screened against IDE, resulting in the identification of 1-hydroxypyridine-2-thione (1,2-HOPTO) as an effective Zn2+-binding scaffold. Screening a focused library of HOPTO compounds identified 3-sulfonamide derivatives of 1,2-HOPTO as inhibitors of IDE (K-i values of similar to 50 mu M). Further structure-activity relationship studies yielded several thiophene-sulfonamide HOPTO derivatives with good, broad-spectrum activity against IDE that have the potential to be useful pharmacological tools for future studies of IDE.

Automated summary

IDE, a mononuclear Zn2+-dependent metalloenzyme, plays a crucial role in the degradation of insulin and various other peptide hormones. Research on IDE inhibitors is important for understanding its role in diseases such as diabetes and Alzheimer's. Several potential IDE inhibitors have been discovered, showing promise as pharmacological tools for future studies.