title: Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.
abstract: Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Charton
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gauriot
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, W421 Chicago, IL, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; INSERM U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, Lille F-59000, France; European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dumont
authors.affiliation: Univ Lille Nord de France, Lille F-59000, France; INSERM U837 Neurodegenerative Diseases and Neuronal Death, Lille F-59000, France; CHRU, Lille F-59000, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Hamdane
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Pottiez
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Landry
authors.affiliation: CDithem Platform/IGM, Paris, France; Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sperandio
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Flipo
authors.affiliation: Univ Lille Nord de France, Lille F-59000, France; INSERM U837 Neurodegenerative Diseases and Neuronal Death, Lille F-59000, France; CHRU, Lille F-59000, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buee
authors.affiliation: Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; INSERM U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, Lille F-59000, France; European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, W421 Chicago, IL, USA.
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France. Electronic address: benoit.deprez@univ-lille2.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France. Electronic address: rebecca.deprez@univ-lille2.fr.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Deprez-Poulain
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D007093:Imidazoles / Q000737:chemistry*; D007339:Insulysin / Q000378:metabolism*; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000085:Acetates; D016229:Amyloid beta-Peptides; D007093:Imidazoles; D054852:Small Molecule Libraries; C029899:imidazole; D007339:Insulysin
keywords: Amyloid-beta peptides; Enzymes; Inhibitors; Medicinal chemistry; Structure–activity relationships; X-ray diffraction
references.citation: PLoS One. 2012;7(2):e31787
references.pmid: 22355395
references.citation: J Med Chem. 2013 Mar 28;56(6):2246-55
references.pmid: 23437776
references.citation: J Mol Biol. 2009 Feb 6;385(5):1556-67
references.pmid: 19073193
references.citation: Hum Mol Genet. 2000 Sep 1;9(14):2149-58
references.pmid: 10958757
references.citation: Protein Expr Purif. 2000 Jun;19(1):91-8
references.pmid: 10833395
references.citation: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8523-7
references.pmid: 22586115
references.citation: Diabetologia. 2009 Aug;52(8):1457-60
references.pmid: 19504084
references.citation: Am J Pathol. 2004 Apr;164(4):1425-34
references.pmid: 15039230
references.citation: Hum Mutat. 2003 Nov;22(5):363-71
references.pmid: 14517947
references.citation: FEBS Lett. 1998 May 8;427(2):153-6
references.pmid: 9607302
references.citation: Neurobiol Dis. 2007 Mar;25(3):686-96
references.pmid: 17207630
references.citation: PLoS One. 2010 May 07;5(5):e10504
references.pmid: 20498699
references.citation: Nature. 2006 Oct 19;443(7113):870-4
references.pmid: 17051221
references.citation: J Biol Chem. 2007 Aug 31;282(35):25453-63
references.pmid: 17613531
references.citation: J Med Chem. 2009 Nov 12;52(21):6790-802
references.pmid: 19821586
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13827-32
references.pmid: 23922390
references.citation: Endocr Res. 1984;10(2):101-12
references.pmid: 6389104
references.citation: Arch Biochem Biophys. 2007 Dec 1;468(1):128-33
references.pmid: 17964527
references.citation: Neurobiol Aging. 2006 Feb;27(2):190-8
references.pmid: 16399206
references.citation: Cell Mol Life Sci. 2006 Nov;63(21):2432-4
references.pmid: 16952049
references.citation: J Mol Biol. 2010 Jan 15;395(2):430-43
references.pmid: 19896952
references.citation: J Biol Chem. 2012 Jan 2;287(1):48-57
references.pmid: 22049080
references.citation: J Biol Chem. 2009 May 22;284(21):14177-88
references.pmid: 19321446
references.citation: Biochem J. 2004 Nov 1;383(Pt. 3):439-46
references.pmid: 15285718
references.citation: FEBS Lett. 1994 May 23;345(1):33-7
references.pmid: 8194595
references.citation: J Biol Chem. 2011 Jul 1;286(26):22711-5
references.pmid: 21576244
references.citation: Science. 2000 Dec 22;290(5500):2302-3
references.pmid: 11125142
references.citation: Cell Mol Life Sci. 2008 Aug;65(16):2574-85
references.pmid: 18470479
references.citation: J Mol Biol. 2011 Feb 25;406(3):454-66
references.pmid: 21185309
references.citation: PLoS One. 2011;6(6):e20864
references.pmid: 21731629
references.citation: Nature. 2007 Feb 22;445(7130):881-5
references.pmid: 17293876
references.citation: PLoS One. 2009;4(4):e5274
references.pmid: 19384407
references.citation: Neuron. 2003 Dec 18;40(6):1087-93
references.pmid: 14687544
references.citation: Curr Drug Metab. 2003 Dec;4(6):461-85
references.pmid: 14683475
references.citation: J Endocrinol. 2003 Jun;177(3):399-405
references.pmid: 12773120
references.citation: Cerebrospinal Fluid Res. 2009 Sep 11;6:11
references.pmid: 19747378
references.citation: Curr Pharm Des. 2009;15(31):3644-55
references.pmid: 19925417
references.citation: J Biomol Screen. 2012 Dec;17(10):1348-61
references.pmid: 22740246