title: 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.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Borhade
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Ulrika
authors.initials: U
authors.lastname: Rosenström
authors.affiliation: Beijer Laboratory, Department of Medicinal Chemistry, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Jonas
authors.initials: J
authors.lastname: Sävmarker
authors.affiliation: 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).
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.affiliation: 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).
authors.forename: Annika
authors.initials: A
authors.lastname: Jenmalm-Jensen
authors.affiliation: 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).
authors.forename: Kristmundur
authors.initials: K
authors.lastname: Sigmundsson
authors.affiliation: 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).
authors.forename: Hanna
authors.initials: H
authors.lastname: Axelsson
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Fredrik
authors.initials: F
authors.lastname: Svensson
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Vivek
authors.initials: V
authors.lastname: Konda
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Christian
authors.initials: C
authors.lastname: Sköld
authors.affiliation: Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University P.O. Box 574, 751 23 Uppsala (Sweden).
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.affiliation: Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, BMC, Uppsala University P.O. Box 591, 751 24 Uppsala (Sweden) E-mail: mathias.hallberg@farmbio.uu.se.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hallberg
keywords: aminopeptidases; arylsulfonamides; cognitive enhancers; insulin-regulated aminopeptidase (IRAP); structure–activity relationships