5524936
doi
10.1021/acs.jmedchem.1c00603
oai:zenodo.org:5524936
user-eu
Annalisa Savardi
Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, 38123 Rome, Italy
Jacopo Manigrasso
Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Alessandra Turci
Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Università degli Studi di Genova, via Balbi, 5, 16126 Genoa, Italy
Corinne Portioli
Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
Giuliana Ottonello
Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
Sine Mandrup Bertozzi
Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
Andrea Armirotti
Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
Andrea Contestabile
Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
Laura Cancedda
Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, 38123 Rome, Italy
Marco De Vivo
Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome
Marco Borgogno
Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
doi:10.1021/acs.jmedchem.1c00603
info:eu-repo/semantics/openAccess
Creative Commons Attribution 4.0 International
https://creativecommons.org/licenses/by/4.0/legalcode
<p>Intracellular chloride concentration [Cl<sup>-</sup>]<sub>i</sub> is defective in several neurological disorders. In neurons, [Cl<sup>-</sup>]<sub>i</sub> is mainly regulated by the action of the Na<sup>+</sup>-K<sup>+</sup>-Cl<sup>-</sup> importer NKCC1 and the K<sup>+</sup>-Cl<sup>-</sup> exporter KCC2. Recently, we have reported the discovery of <strong>ARN23746</strong> as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, <strong>ARN23746</strong> is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on <strong>ARN23746</strong> and other promising derivatives. In particular, we present compound <strong>40</strong> (<strong>ARN24092</strong>) as a backup/follow-up lead with <em>in vivo</em> efficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.</p>
Zenodo
2021-07-22
info:eu-repo/semantics/article
5524935
user-eu
award_title=Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders.; award_number=843239; award_identifiers_scheme=url; award_identifiers_identifier=https://cordis.europa.eu/projects/843239; funder_id=00k4n6c32; funder_name=European Commission;
award_title=Rescuing Cognitive Deficits in Neurodevelopmental Disorders by Gene Editing in Brain Development: the Case of Down Syndrome; award_number=725563; award_identifiers_scheme=url; award_identifiers_identifier=https://cordis.europa.eu/projects/725563; funder_id=00k4n6c32; funder_name=European Commission;
1632491304.67891
3489331
md5:70d3ddc3065d0210eccab92edde8af27
https://zenodo.org/records/5524936/files/Borgogno et al 2021.pdf
19249749
md5:2a57742f369d512c0ee8fd62f8c26084
https://zenodo.org/records/5524936/files/Borgogno et al 2021 SI.pdf
public
10.1021/acs.jmedchem.1c00603
Is identical to
doi
J Med Chem
64
14
10203-10229
2021-07-22