ChemistryOpen | |
Inhibition of Insulin‐Regulated Aminopeptidase (IRAP) by Arylsulfonamides | |
Dr. Sanjay R. Borhade1  Dr. Ulrika Rosenström1  Dr. Jonas Sävmarker3  Dr. Thomas Lundbäck2  Dr. Annika Jenmalm-Jensen2  Dr. Kristmundur Sigmundsson2  Hanna Axelsson2  Fredrik Svensson1  Dr. Vivek Konda1  Dr. Christian Sköld1  Prof. Mats Larhed4  | |
[1] Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, 751 23 Uppsala (Sweden);Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 77 (Sweden);Beijer Laboratory, Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, 751 23 Uppsala (Sweden);Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, P.O. Box 574, 751 23 Uppsala (Sweden) | |
关键词: aminopeptidases; arylsulfonamides; insulin-regulated aminopeptidase (IRAP); structure–activity relationships; cognitive enhancers; | |
DOI : 10.1002/open.201402027 | |
来源: Wiley | |
【 摘 要 】
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.Abstract
【 授权许可】
CC BY-NC
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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