CC BY 4.0 · Synlett
DOI: 10.1055/a-2562-7204
letter
Small Molecules in Medicinal Chemistry

Benzylhydroxamic Acids as IRAP Inhibitors: Sulfonamide Variations

Julia Beveridge 
a   The Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, 751 23 Uppsala, Sweden
,
Marcus Söderström
a   The Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, 751 23 Uppsala, Sweden
,
Lorenzo Jacopo Ilic Balestri
b   Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, 751 23 Uppsala, Sweden
,
Rubén Prieto-Díaz
c   Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, Box 596, 751 24, Uppsala, Sweden
,
Hugo Gutierrez-de-Teran
c   Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, Box 596, 751 24, Uppsala, Sweden
d   Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, s/n, 33011 Oviedo, Asturias, Spain
,
Luke R Odell 
b   Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, 751 23 Uppsala, Sweden
,
Mathias Hallberg
e   The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, Biomedical Centre, Uppsala University, Box 591, 751 24 Uppsala, Sweden
,
Mats Larhed  ∗
a   The Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, 751 23 Uppsala, Sweden
,
Johan Gising  ∗
a   The Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, 751 23 Uppsala, Sweden
› Author Affiliations
Computations were performed with resources provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS), partially funded by the Vetenskapsrådet (Swedish Research Council) through grant agreement no. 2022-06725, the Kjell och Märta Beijers Stiftelse, Vetenskapsrådet (Swedish Research Council) through grants no. 2021-03293 and 2022-04831 and the Swedish Brain Foundation through grant FO2024-0317-HK-70. Additional support is acknowledged from the Swedish Strategic Research Program eSSENCE.
› Further Information
  Permissions and Reprints All articles of this category


Abstract

Small-molecule inhibitors of the zinc metalloprotease insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), are a promising new class of potential cognitive enhancers for the treatment of neurodegenerative disorders such as Alzheimer’s disease. Previous studies identified a series of sulfonamide-substituted benzylhydroxamic acids with fair BBB permeability, no indication of efflux and subnanomolar potency. We herein report our further structural optimization of this compound series focusing on various alterations to the sulfonamide group. Notably, introduction of dihydropyridopyrimidine provided the most active small-molecule inhibitor compound reported to date, with an IC50 value of 34 nM. Molecular modeling studies, based on free energy perturbation simulations, show that the accommodation of the explored substituents on the binding mode proposed explain the experimental SAR herein reported and provide a rationale for the enhanced affinity of the optimized compounds.

Key words

IRAP - cognitive enhancement - enzyme inhibitor - hydro­xamic acid - free energy perturbation (FEP)

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2562-7204.
  • Supporting Information


Publication History

Received: 31 January 2025

Accepted: 19 March 2025

Accepted Manuscript online:
19 March 2025

Article published online:
15 April 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Tsujimoto M, Hattori A. Biochim. Biophys. Acta, Proteins Proteomics 2005; 1751: 9
    Search in Google Scholar
  • 2 Georgiadis D, Ziotopoulou A, Kaloumenou E, Lelis A, Papasava A. Front. Pharmacol. 2020; 11: 585838
    PubMedSearch in Google Scholar
  • 3 Hallberg M, Larhed M. Front. Pharmacol. 2020; 11: 590855
    PubMedSearch in Google Scholar
  • 4 Barlow N, Thompson PE. Front. Pharmacol. 2020; 11: 585930
    PubMedSearch in Google Scholar
  • 5 Wallis MG, Lankford MF, Keller SR. Am. J. Physiol. Endocrinol. Metab. 2007; 293: E1092
    PubMedSearch in Google Scholar
  • 6 Mizutani S. Nagoya J. Med. Sci. 1998; 61: 85
    PubMedSearch in Google Scholar
  • 7 Herbst JJ, Ross SA, Scott HM, Bobin SA, Morris NJ, Lienhard GE, Keller SR. Am. J. Physiol. 1997; 272: E600
    PubMedSearch in Google Scholar
  • 8 Matsumoto H, Rogi T, Yamashiro K, Kodama S, Tsuruoka N, Hattori A, Takio K, Mizutani S, Tsujimoto M. Eur. J. Biochem. 2000; 267: 46
    PubMedSearch in Google Scholar
  • 9 Matsumoto H, Nagasaka T, Hattori A, Rogi T, Tsuruoka N, Mizutani S, Tsujimoto M. Eur. J. Biochem. 2001; 268: 3259
    PubMedSearch in Google Scholar
  • 10 Alescio-Lautier B, Paban V, Soumireu-Mourat B. Eur. J. Pharmacol. 2000; 405: 63
    PubMedSearch in Google Scholar
  • 11 Seyer B, Diwakarla S, Burns P, Hallberg A, Grӧnbladh A, Hallberg M, Chai SY. J. Neurochem. 2020; 153: 485
    PubMedSearch in Google Scholar
  • 12 Albiston AL, Morton CJ, Ng HL, Pham V, Yeatman HR, Ye S, Fernando RN, De Bundel D, Ascher DB, Mendelsohn FA. O, Parker MW, Chai SY. FASEB J. 2008; 22: 4209
    PubMedSearch in Google Scholar
  • 13 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 2014; 3: 256
    PubMedSearch in Google Scholar
  • 14 Diwakarla S, Nylander E, Grönbladh A, Vanga SR, Shamsudin Y, Gutiérrez-de-Terán H, Sävmarker J, Ng L, Pham V, Lundbäck T, Jenmalm-Jensen A, Svensson R, Artursson P, Zelleroth S, Engen K, Rosenström U, Larhed M, Åqvist J, Chai SY, Hallberg M. ACS Chem. Neurosci. 2016; 7: 1383
    PubMedSearch in Google Scholar
  • 15 Papakyriakou A, Zervoudi E, Tsoukalidou S, Mauvais F.-X, Sfyroera G, Mastellos DC, van Endert P, Theodorakis EA, Vourloumis D, Stratikos E. J. Med. Chem. 2015; 58: 1524
    PubMedSearch in Google Scholar
  • 16 Kokkala P, Mpakali A, Mauvais F.-X, Papakyriakou A, Daskalaki I, Petropoulou I, Kavvalou S, Papathanasopoulou M, Agrotis S, Fonsou T.-M, van Endert P, Stratikos E, Georgiadis D. J. Med. Chem. 2016; 59: 9107
    PubMedSearch in Google Scholar
  • 17 Engen K, Vanga SR, Lundbäck T, Agalo F, Konda V, Jensen AJ, Åqvist J, Gutiérrez-de-Terán H, Hallberg M, Larhed M, Rosenström U. ChemistryOpen 2020; 9: 325
    PubMedSearch in Google Scholar
  • 18 Vourloumis D, Mavridis I, Athanasoulis A, Temponeras I, Koumantou D, Giastas P, Mpakali A, Magrioti V, Leib J, van Endert P, Stratikos E, Papakyriakou A. J. Med. Chem. 2022; 65: 10098
    PubMedSearch in Google Scholar
  • 19 Engen K, Lundbäck T, Yadav A, Puthiyaparambath S, Rosenström U, Gising J, Jenmalm-Jensen A, Hallberg M, Larhed M. Int. J. Mol. Sci. 2024; 25: 2516
    PubMedSearch in Google Scholar
  • 20 Gising J, Honarnejad S, Bras M, Baillie GL, McElroy SP, Jones PS, Morrison A, Beveridge J, Hallberg M, Larhed M. Int. J. Mol. Sci. 2024; 25: 4084
    PubMedSearch in Google Scholar
  • 21 Beveridge J, Söderström M, Prieto-Díaz R, Gutierrez-de-Teran H, Odell LR, Hallberg M, Larhed M, Gising J. Eur. J. Med. Chem. Rep. 2024; 12: 100215
    Search in Google Scholar
  • 22 Hermans SJ, Ascher DB, Hancock NC, Holien JK, Michell BJ, Chai SY, Morton CJ, Parker MW. Protein Sci. 2015; 24: 190
    PubMedSearch in Google Scholar
  • 23 Lu C, Wu C, Ghoreishi D, Chen W, Wang L, Damm W, Ross GA, Dahlgren MK, Russell E, Von Bargen CD, Abel R, Friesner RA, Harder ED. J. Chem. Theory Comput. 2021; 17: 4291
    PubMedSearch in Google Scholar
  • 24 Jespers W, Esguerra M, Åqvist J, Gutiérrez-de-Terán H. J. Cheminform. 2019; 11: 26
    PubMedSearch in Google Scholar
  • 25 Bauer P, Barrozo A, Purg M, Amrein BA, Esguerra M, Wilson PB, Major DT, Åqvist J, Kamerlin SC. L. SoftwareX 2018; 7: 388
    Search in Google Scholar
  • 26 Edwards MP, Price DA. Annu. Rep. Med. Chem. 2010; 45: 380
    Search in Google Scholar