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Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors

Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffe...

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Autores principales: Engen, Karin, Vanga, Sudarsana Reddy, Lundbäck, Thomas, Agalo, Faith, Konda, Vivek, Jensen, Annika Jenmalm, Åqvist, Johan, Gutiérrez‐de‐Terán, Hugo, Hallberg, Mathias, Larhed, Mats, Rosenström, Ulrika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050655/
https://www.ncbi.nlm.nih.gov/pubmed/32154052
http://dx.doi.org/10.1002/open.201900344
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author Engen, Karin
Vanga, Sudarsana Reddy
Lundbäck, Thomas
Agalo, Faith
Konda, Vivek
Jensen, Annika Jenmalm
Åqvist, Johan
Gutiérrez‐de‐Terán, Hugo
Hallberg, Mathias
Larhed, Mats
Rosenström, Ulrika
author_facet Engen, Karin
Vanga, Sudarsana Reddy
Lundbäck, Thomas
Agalo, Faith
Konda, Vivek
Jensen, Annika Jenmalm
Åqvist, Johan
Gutiérrez‐de‐Terán, Hugo
Hallberg, Mathias
Larhed, Mats
Rosenström, Ulrika
author_sort Engen, Karin
collection PubMed
description Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non‐peptide IRAP inhibitors derived from a spiro‐oxindole dihydroquinazolinone screening hit (pIC(50) 5.8). The compounds were synthesized either by a simple microwave (MW)‐promoted three‐component reaction, or by a two‐step one‐pot procedure. For decoration of the oxindole ring system, rapid MW‐assisted Suzuki‐Miyaura cross‐couplings (1 min) were performed. A small improvement of potency (pIC(50) 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S‐configuration of the spiro‐oxindole dihydroquinazolinones accounts for the inhibition of IRAP.
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spelling pubmed-70506552020-03-09 Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors Engen, Karin Vanga, Sudarsana Reddy Lundbäck, Thomas Agalo, Faith Konda, Vivek Jensen, Annika Jenmalm Åqvist, Johan Gutiérrez‐de‐Terán, Hugo Hallberg, Mathias Larhed, Mats Rosenström, Ulrika ChemistryOpen Full Papers Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non‐peptide IRAP inhibitors derived from a spiro‐oxindole dihydroquinazolinone screening hit (pIC(50) 5.8). The compounds were synthesized either by a simple microwave (MW)‐promoted three‐component reaction, or by a two‐step one‐pot procedure. For decoration of the oxindole ring system, rapid MW‐assisted Suzuki‐Miyaura cross‐couplings (1 min) were performed. A small improvement of potency (pIC(50) 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S‐configuration of the spiro‐oxindole dihydroquinazolinones accounts for the inhibition of IRAP. John Wiley and Sons Inc. 2020-03-02 /pmc/articles/PMC7050655/ /pubmed/32154052 http://dx.doi.org/10.1002/open.201900344 Text en © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Full Papers
Engen, Karin
Vanga, Sudarsana Reddy
Lundbäck, Thomas
Agalo, Faith
Konda, Vivek
Jensen, Annika Jenmalm
Åqvist, Johan
Gutiérrez‐de‐Terán, Hugo
Hallberg, Mathias
Larhed, Mats
Rosenström, Ulrika
Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors
title Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors
title_full Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors
title_fullStr Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors
title_full_unstemmed Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors
title_short Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors
title_sort synthesis, evaluation and proposed binding pose of substituted spiro‐oxindole dihydroquinazolinones as irap inhibitors
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050655/
https://www.ncbi.nlm.nih.gov/pubmed/32154052
http://dx.doi.org/10.1002/open.201900344
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