PMID- 33686743
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20220124
IS  - 1860-7187 (Electronic)
IS  - 1860-7179 (Print)
IS  - 1860-7179 (Linking)
VI  - 16
IP  - 11
DP  - 2021 Jun 7
TI  - Hydroxypyridinethione Inhibitors of Human Insulin-Degrading Enzyme.
PG  - 1775-1787
LID - 10.1002/cmdc.202100111 [doi]
AB  - 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 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 Zn(2+) ion have yet to 
      be fully explored. In an effort to discover new, zinc-targeting inhibitors of 
      IDE, a library of  approximately 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  approximately 50 muM). 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.
CI  - (c) 2021 Wiley-VCH GmbH.
FAU - Adamek, Rebecca N
AU  - Adamek RN
AD  - Department of Chemistry and Biochemistry, University of California, San Diego, La 
      Jolla, CA 92093, USA.
FAU - Suire, Caitlin N
AU  - Suire CN
AD  - Institute for Memory Impairments and Neurological Disorders, University of 
      California, Irvine, Irvine, CA 92697, USA.
FAU - Stokes, Ryjul W
AU  - Stokes RW
AD  - Department of Chemistry and Biochemistry, University of California, San Diego, La 
      Jolla, CA 92093, USA.
FAU - Brizuela, Monica K
AU  - Brizuela MK
AD  - Institute for Memory Impairments and Neurological Disorders, University of 
      California, Irvine, Irvine, CA 92697, USA.
FAU - Cohen, Seth M
AU  - Cohen SM
AUID- ORCID: 0000-0002-5233-2280
AD  - Department of Chemistry and Biochemistry, University of California, San Diego, La 
      Jolla, CA 92093, USA.
FAU - Leissring, Malcolm A
AU  - Leissring MA
AD  - Institute for Memory Impairments and Neurological Disorders, University of 
      California, Irvine, Irvine, CA 92697, USA.
LA  - eng
GR  - R01 GM115617/GM/NIGMS NIH HHS/United States
GR  - U.C. San Diego Chemistry and Biochemistry Mass Spectrometry Facility/
GR  - T32 GM112584/GM/NIGMS NIH HHS/United States
GR  - DGE-1650112/Graduate Research Fellowship Program (GRFP) from the National Science 
      Foundation/
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210331
PL  - Germany
TA  - ChemMedChem
JT  - ChemMedChem
JID - 101259013
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Thiones)
RN  - EC 3.4.24.56 (Insulysin)
SB  - IM
MH  - Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Humans
MH  - Insulysin/*antagonists & inhibitors/metabolism
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Pyridines/chemical synthesis/chemistry/*pharmacology
MH  - Thiones/chemical synthesis/chemistry/*pharmacology
PMC - PMC8627785
MID - NIHMS1758398
OTO - NOTNLM
OT  - fragment-based drug discovery
OT  - high-throughput screening
OT  - insulin-degrading enzymes
OT  - medicinal chemistry
OT  - metalloenzymes
COIS- Conflict of Interests S.M.C. is a cofounder of and has an equity interest in 
      Cleave Therapeutics and Forge Therapeutics, companies that might potentially 
      benefit from the research results. S.M.C. also serves on the Scientific Advisory 
      Board for Forge Therapeutics. The terms of this arrangement have been reviewed 
      and approved by the University of California, San Diego in accordance with its 
      conflict of interests policies.
EDAT- 2021/03/10 06:00
MHDA- 2022/01/27 06:00
PMCR- 2021/11/28
CRDT- 2021/03/09 06:17
PHST- 2021/02/28 00:00 [revised]
PHST- 2021/02/12 00:00 [received]
PHST- 2021/03/10 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/03/09 06:17 [entrez]
PHST- 2021/11/28 00:00 [pmc-release]
AID - 10.1002/cmdc.202100111 [doi]
PST - ppublish
SO  - ChemMedChem. 2021 Jun 7;16(11):1775-1787. doi: 10.1002/cmdc.202100111. Epub 2021 
      Mar 31.