Inhibition of Insulin‐Regulated Aminopeptidase (IRAP) by Arylsulfonamides

ChemistryOpen

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 】

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.

【 授权许可】

CC BY-NC   
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

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