Inhibition of Insulin‐Regulated Aminopeptidase (IRAP) by Arylsulfonamides

Abstract

The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure–activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

“…Both potent and specific drug-like IRAP inhibitors (Borhade et al, 2014;Mountford et al, 2014), some with proven effects in vivo (Albiston et al, , 2011, and inhibitors with more peptidic character (Kobori et al, , 1998Wolfe, 2002;Axen et al, 2006;Axen et al, 2007;Andersson et al, 2008;Lukaszuk et al, 2008Lukaszuk et al, , 2009Hallberg, 2009) have been disclosed by us and others. We use an approach to discover efficient Ang IV peptidomimetics that relies on stepwise alterations of Ang IV by applying various cyclization procedures to restrict conformational flexibility and to allow determination of the bioactive conformation of Ang IV when it binds to IRAP (Axen et al, 2006(Axen et al, , 2007.…”

3,4-Diaminobenzoic Acid Derivatives as Inhibitors of the Oxytocinase Subfamily of M1 Aminopeptidases with Immune-Regulating Properties

“…32 Recently, a series of arylsulfonamides was identified as being moderate inhibitors of IRAP, with the most potent exhibiting IC 50 = 1.1 μM. 33 These IRAP inhibitors, however, have either not been tested for their ability to inhibit ERAP1 and ERAP2 or have been tested and found not to be active. 31 As a result, the 3,4-diaminobenzoic acid derivatives described here appear to constitute not only an alternative potent chemical tool for controlling APA activity but also one with very good selectivity properties.…”

Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening

“…6a). Whereas the further SAR exploration for 7 has been published, 36 efforts are still ongoing to further expand the chemistry and SAR around 2 and 5 (to be published elsewhere). It should be noted that visual precipitation is observed at the highest test concentrations (>50 mM) for both compounds 2 and L-5, and especially for 2 this results in an elevated background absorbance and on occasion, the appearance of partial inhibition.…”

“…Synthetic protocols are already published for compounds 2 35 , 5 48 , and 7. 36 In the library, compound 5 was epimeric at the C2 position of the pyrrolidine, but we chose to synthesize the compound with S-chirality since this corresponds to the natural amino acid L-proline. Evaluation of the IRAP inhibitory activity of this stereochemically pure isomer of 5 proved to be in the same order of magnitude as the hit compound (see Table 3 ).…”