300804-20-0Relevant articles and documents
Structure-activity relationships of imidazole-derived 2-[ N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
Charton, Julie,Gauriot, Marion,Totobenazara, Jane,Hennuyer, Nathalie,Dumont, Julie,Bosc, Damien,Marechal, Xavier,Elbakali, Jamal,Herledan, Adrien,Wen, Xiaoan,Ronco, Cyril,Gras-Masse, Helene,Heninot, Antoine,Pottiez, Virginie,Landry, Valerie,Staels, Bart,Liang, Wenguang G.,Leroux, Florence,Tang, Wei-Jen,Deprez, Benoit,Deprez-Poulain, Rebecca
, p. 547 - 567 (2015/03/18)
Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a 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-a 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.
Nickel(II) complexes with N-aralkyliminodiacetic acids: Preparation, spectroscopic, structural and thermal characterization
Smre?ki, Neven,Kukovec, Boris-Marko,Dakovi?, Marijana,Popovi?, Zora
, p. 122 - 129 (2013/07/25)
The reactions of N-aralkyl derivatives of iminodiacetic acid (H 2Bnida, H2Peida, H2Ppida, o-H2Cbida, Bn = benzyl, Pe = 2-phenylethyl, Pp = 3-phenylprop-1-yl, o-Cb = o-chlorobenzyl) with nickel(II) chloride hexahydrate or nickel(II) acetate tetrahydrate in aqueous solutions were studied. Five new nickel(II) complexes [Ni(Bnida)(H 2O)3]·H2O (1), [Ni(Peida)(H 2O)3] (2), [Ni(Ppida)(H2O)3] ·H2O (3a), [Ni(Ppida)(H2O)3] (3b) and [Ni(o-Cbida)(H2O)3] (4) were prepared and characterized by infrared spectroscopy and thermal analysis (TGA-DTA). The crystal structures of 1 and 3b were determined by single-crystal X-ray structural analysis. The octahedral coordination environment around the nickel(II) ion in 1 and 3b consists of an O,N,O′-tridentate N-aralkyliminodiacetate ion and three water molecules arranged in a fac-position. The molecules in the crystal structures of 1 and 3b are connected into a complicated hydrogen-bonded 2D network, dominated by the O-H?O hydrogen bonds. These 2D networks are in turn assembled into a 3D architecture only by weak van der Waals interactions.