Borhade SR, Rosenström U, Sävmarker J, Lundbäck T, Jenmalm-Jensen A, Sigmundsson K, Axelsson H, Svensson F, Konda V, Sköld C, Larhed M, Hallberg M
ChemistryOpen 3 (6) 256-263 [2014-12-00; online 2014-11-21]
The inhibition of insulin-regulated aminopeptidase (IRAP, EC 220.127.116.11) 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.