{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:32:19Z","timestamp":1776918739373,"version":"3.51.2"},"reference-count":42,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM115617"],"award-info":[{"award-number":["R01GM115617"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2021,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Insulin\u2010degrading enzyme (IDE) is a human mononuclear Zn<jats:sup>2+<\/jats:sup>\u2010dependent 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 \u03b2\u2010protein. As such, the study of IDE inhibition is highly relevant to deciphering the role of IDE in conditions such as type\u20102 diabetes mellitus and Alzheimer disease. There have been few reported IDE inhibitors, and of these, inhibitors that directly target the active\u2010site Zn<jats:sup>2+<\/jats:sup> ion have yet to be fully explored. In an effort to discover new, zinc\u2010targeting inhibitors of IDE, a library of \u223c350 metal\u2010binding pharmacophores was screened against IDE, resulting in the identification of 1\u2010hydroxypyridine\u20102\u2010thione (1,2\u2010HOPTO) as an effective Zn<jats:sup>2+<\/jats:sup>\u2010binding scaffold. Screening a focused library of HOPTO compounds identified 3\u2010sulfonamide derivatives of 1,2\u2010HOPTO as inhibitors of IDE (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values of \u223c50\u2005\u03bcM). Further structure\u2010activity relationship studies yielded several thiophene\u2010sulfonamide HOPTO derivatives with good, broad\u2010spectrum activity against IDE that have the potential to be useful pharmacological tools for future studies of IDE.<\/jats:p>","DOI":"10.1002\/cmdc.202100111","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T21:55:09Z","timestamp":1615240509000},"page":"1776-1788","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hydroxypyridinethione Inhibitors of Human Insulin\u2010Degrading Enzyme"],"prefix":"10.1002","volume":"16","author":[{"given":"Rebecca N.","family":"Adamek","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of California, San Diego  La Jolla CA 92093 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlin N.","family":"Suire","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders University of California, Irvine  Irvine CA 92697 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryjul W.","family":"Stokes","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of California, San Diego  La Jolla CA 92093 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica K.","family":"Brizuela","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders University of California, Irvine  Irvine CA 92697 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5233-2280","authenticated-orcid":false,"given":"Seth M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of California, San Diego  La Jolla CA 92093 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm A.","family":"Leissring","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders University of California, Irvine  Irvine CA 92697 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