2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
14 Oct 2021
14 Oct 2021
Historique:
received:
21
07
2021
entrez:
21
10
2021
pubmed:
22
10
2021
medline:
22
10
2021
Statut:
epublish
Résumé
Different five-membered nitrogen-containing heteroaromatics in the position of the typical electrophilic group in prolyl oligopeptidase (PREP) inhibitors were investigated and compared to tetrazole. The 2-imidazoles were highly potent inhibitors of the proteolytic activity. The binding mode for the basic imidazole was studied by molecular docking as it was expected to differ from the acidic tetrazole. A new putative noncovalent binding mode with an interaction to His680 was found for the 2-imidazoles. Inhibition of the proteolytic activity did not correlate with the modulating effect on protein-protein-interaction-derived functions of PREP (i.e., dimerization of alpha-synuclein and autophagy). Among the highly potent PREP inhibiting 2-imidazoles, only one was also a potent modulator of PREP-catalyzed alpha-synuclein dimerization, indicating that the linker length on the opposite side of the molecule from the five-membered heteroaromatic is critical for the disconnected structure-activity relationships.
Identifiants
pubmed: 34671446
doi: 10.1021/acsmedchemlett.1c00399
pmc: PMC8521653
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1578-1584Informations de copyright
© 2021 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
Références
J Biol Chem. 2015 Feb 20;290(8):5117-5126
pubmed: 25555914
Biochem Pharmacol. 2002 Aug 1;64(3):463-71
pubmed: 12147298
Science. 1971 Aug 27;173(3999):827-9
pubmed: 5572174
Angew Chem Int Ed Engl. 2012 Dec 21;51(52):13159-62
pubmed: 23161532
Bioorg Med Chem. 2005 Dec 1;13(23):6309-23
pubmed: 16213736
J Biol Chem. 1976 Dec 10;251(23):7593-9
pubmed: 12173
J Org Chem. 2014 Oct 3;79(19):9423-6
pubmed: 25215450
Cell. 1998 Jul 24;94(2):161-70
pubmed: 9695945
Mol Cell. 2016 Nov 17;64(4):835-849
pubmed: 27818143
Sci Rep. 2017 May 26;7(1):2456
pubmed: 28550305
Neuropeptides. 2007 Feb;41(1):1-24
pubmed: 17196652
ChemMedChem. 2014 Jul;9(7):1378-86
pubmed: 24729513
Bioorg Med Chem Lett. 2010 Feb 15;20(4):1436-9
pubmed: 20097068
Bioorg Med Chem Lett. 2008 Aug 1;18(15):4360-3
pubmed: 18606544
J Med Chem. 1994 Oct 14;37(21):3492-502
pubmed: 7932578
J Neurochem. 1982 Apr;38(4):1151-4
pubmed: 7038048
Chem Pharm Bull (Tokyo). 1993 Sep;41(9):1583-8
pubmed: 8221972
J Neurosci. 2016 Dec 7;36(49):12485-12497
pubmed: 27927963
Br J Pharmacol. 2012 Jun;166(3):1097-113
pubmed: 22233220
ACS Med Chem Lett. 2019 Nov 11;10(12):1635-1640
pubmed: 31857839
Neurosci Lett. 2011 Sep 15;502(2):107-11
pubmed: 21820035
Neurobiol Dis. 2014 Aug;68:1-15
pubmed: 24746855
Pharmacol Res. 2020 Jan;151:104558
pubmed: 31759088
J Med Chem. 2004 Nov 4;47(23):5605-7
pubmed: 15509157
Biomed Pharmacother. 2020 Aug;128:110253
pubmed: 32447211
Drug News Perspect. 2007 Jun;20(5):293-305
pubmed: 17878957
Biochimie. 2012 Jun;94(6):1398-411
pubmed: 22484394