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Hydroxypyridinethione Inhibitors of Human Insulin‐Degrading Enzyme
Author(s) -
Adamek Rebecca N.,
Suire Caitlin N.,
Stokes Ryjul W.,
Brizuela Monica K.,
Cohen Seth M.,
Leissring Malcolm A.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100111
Subject(s) - human insulin , insulin degrading enzyme , enzyme , insulin , chemistry , biochemistry , pharmacology , medicine
Insulin‐degrading enzyme (IDE) is a human mononuclear Zn 2+ ‐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 Zn 2+ 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 Zn 2+ ‐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 ∼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.