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Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome.

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Title: Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome.
Authors: Borgogno M; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Savardi A; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Dulbecco Telethon Institute, 38123 Rome, Italy., Manigrasso J; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Turci A; 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., Portioli C; 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., Ottonello G; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Bertozzi SM; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Armirotti A; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Contestabile A; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Cancedda L; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Dulbecco Telethon Institute, 38123 Rome, Italy., De Vivo M; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Source: Journal of medicinal chemistry [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 10203-10229. Date of Electronic Publication: 2021 Jun 17.
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Language: English
Journal Info: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Imprint Name(s): Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms: Drug Design*, Down Syndrome/*drug therapy , Solute Carrier Family 12, Member 2/*metabolism, Animals ; Cells, Cultured ; Dose-Response Relationship, Drug ; Down Syndrome/metabolism ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Structure ; Structure-Activity Relationship
Abstract: Intracellular chloride concentration [Cl - ] i is defective in several neurological disorders. In neurons, [Cl - ] i is mainly regulated by the action of the Na + -K + -Cl - importer NKCC1 and the K + -Cl - exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 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 ARN23746 and other promising derivatives. In particular, we present compound 40 ( ARN24092 ) as a backup/follow-up lead with in vivo 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.
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Substance Nomenclature: 0 (SLC12A2 protein, human)
0 (Solute Carrier Family 12, Member 2)
Entry Date(s): Date Created: 20210617 Date Completed: 20211006 Latest Revision: 20211006
Update Code: 20221216
PubMed Central ID: PMC8311653
DOI: 10.1021/acs.jmedchem.1c00603
PMID: 34137257
Database: MEDLINE
Description
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.1c00603