Hydroxypyridinethione Inhibitors of Human Insulin-Degrading Enzyme
| Autor: | Adamek, Rebecca N, Suire, Caitlin N, Stokes, Ryjul W, Brizuela, Monica K, Cohen, Seth M, Leissring, Malcolm A |
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| Rok vydání: | 2021 |
| Předmět: |
metalloenzymes
Molecular Structure Pyridines Medicinal & Biomolecular Chemistry Diabetes Organic Chemistry Thiones Molecular Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Pharmacology and Pharmaceutical Sciences Insulysin high-throughput screening Brain Disorders Medicinal and Biomolecular Chemistry Models medicinal chemistry Acquired Cognitive Impairment Humans Enzyme Inhibitors fragment-based drug discovery insulin-degrading enzymes Metabolic and endocrine |
| Zdroj: | ChemMedChem, vol 16, iss 11 |
| Popis: | 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 β-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 ∼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 (Ki values of ∼50 μM). 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. |
| Databáze: | OpenAIRE |
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