Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome
Creators
- 1. Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
- 2. Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, 38123 Rome, Italy
- 3. 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
- 4. 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
- 5. Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- 6. Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
Description
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.
Files
Borgogno et al 2021 SI.pdf
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Additional details
Related works
- Is identical to
- Journal article: 10.1021/acs.jmedchem.1c00603 (DOI)
Funding
- 3D NKCC1 – Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders. 843239
- European Commission
- GenEdiDS – Rescuing Cognitive Deficits in Neurodevelopmental Disorders by Gene Editing in Brain Development: the Case of Down Syndrome 725563
- European Commission