title: Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.
abstract: Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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; 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: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Jane
authors.initials: J
authors.lastname: Totobenazara
authors.affiliation: 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, F-59000, Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Damien
authors.initials: D
authors.lastname: Bosc
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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; 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: Jamal
authors.initials: J
authors.lastname: Elbakali
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Adrien
authors.initials: A
authors.lastname: Herledan
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Xiaoan
authors.initials: X
authors.lastname: Wen
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Cyril
authors.initials: C
authors.lastname: Ronco
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Helene
authors.initials: H
authors.lastname: Gras-Masse
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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: Antoine
authors.initials: A
authors.lastname: Heninot
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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; 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: 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, F-59000, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, W421 Chicago, IL, USA.
authors.forename: Wenguang G
authors.initials: WG
authors.lastname: Liang
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Lille, 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; 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; 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: D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010069:Oxadiazoles; D007339:Insulysin
keywords: Amyloid-beta peptides; Docking; Enzymes; Inhibitors; Structure–activity relationships; X-ray diffraction