The First Potent Inhibitors for Human Glutaminyl Cyclase:  Synthesis and Structure−Activity Relationship

Abstract

The first effective inhibitors for human glutaminyl cyclase (QC) are described. The structures are developed by applying a ligand-based optimization approach starting from imidazole. Screening of derivatives of that heterocycle led to compounds of the imidazol-1-yl-alkyl thiourea type as a lead scaffold. A library of thiourea derivatives was synthesized, resulting in an inhibitory improvement by 2 orders of magnitude, leading to 1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thiourea as a potent inhibitor. Systematic exploitation of the scaffold revealed a strong impact on the inhibitory efficacy and resulted in the development of imidazole-propyl-thioamides as another new class of potent inhibitors. A flexible alignment of the most potent compounds of the thioamide and thiourea class and a QC substrate revealed a good match of characteristic features of the molecules, which suggests a similar binding mode of both inhibitors and the substrate to the active site of QC.

Structure and Toxicity of the Prefibrillar Aggregation States of Beta Peptides in Alzheimer’s Disease

“…Recently, it was demonstrated that, in similar initial buffer conditions and using three different techniques (flow cytometry, ThT fluorescence and circular dichroism), these N-terminal modified peptides aggregate much faster than the fulllength Aβ (D'Arrigo et al, 2009;Shilling et al, 2006). Altogether, the aggregation kinetics of Apy3-42 was found 20-250 by cytometry and ThT fluorescence (Shilling et al, 2006) and more than 30 times by CD (D'Arrigo et al, 2009) faster than that of A1-42 respectively, depending upon the assay method. The oligomers that form β-structure rapidly are found to be more toxic (D'Arrigo et al, 2009;Mastrangelo et al, 2006;Shilling et al, 2006).…”

“…Recently, the faster aggregation kinetics after incubation time of the N-terminal and pyromodified peptides relative to the full length Aβ, were demonstrated together with significant morthological differences in the pure or mixed aggregation states (D'Arrigo et al, 2009;Shilling et al, 2006). Demuth and coll.…”

“…gave indications that prevention of formation of pyroglutamate-modified N-terminally truncated Aβs, such as Aβpy3-42, by inhibition of glutaminyl cyclase, may represent a new therapeutic strategy for alleviating amyloidoses (Shilling et al, 2008). In general, N-terminal pyroglutamyl modifications increase the aggregation propensity and also enhances resistance to degradation by proteases (Shilling et al, 2004(Shilling et al, , 2006. Prevention of formation of pyroglutamate-modified N-terminally truncated Aβs may be beneficial for AD patients.…”

Novel phenyl(thio)ureas bearing (thio)oxothiazoline group as potential BACE-1 inhibitors: synthesis and biological evaluation

“…The search of BACE-1 inhibitors is a very active field of research [24][25][26][27][28][29][30][31] . Arylthioureas have been recently described in several patents as potentially active scaffolds for neurodegenerative diseases including Alzheimer 32,33 . Moreover, (thio)oxothiazolphenyl heterocycles represent a privileged moiety very often encountered in bioactive molecules utilized for the treatment of several pathologies including neurodegenerative diseases 34,35 .…”

Can Small Molecule Inhibitors of Glutaminyl Cyclase Be Used as a Therapeutic for Alzheimer'S Disease?

“…To inhibit the activity of QC, a few small molecule QC inhibitors have been reported [12][13][14][15][16]. These chemicals contain an aromatic motif tethered to an imidazole moiety, where the aromatic ring matches the hydrophobic space at the entrance of the active site and the imidazole moiety binds the catalytic zinc ion at the bottom of the pocket.…”