Alterations in the expression of the Cl^- importer Na-K-2Cl co-transporter-1 (NKCC1) and the exporter K-Cl co-transporter 2 (KCC2) lead to impaired intracellular chloride concentration in neurons and imbalanced excitation/inhibition in the brain. These alterations have been observed in several neurological disorders (e.g., Down syndrome and autism). Recently, we have reported the discovery of the selective NKCC1 inhibitor "compound ARN23746" for the treatment of Down syndrome and autism in mouse models. Here, we report on an extensive preclinical characterization of ARN23746 toward its development as a clinical candidate. ARN23746 shows an overall excellent metabolism profile and good brain penetration. Moreover, ARN23746 is effective in rescuing cognitive impairment in Down syndrome mice upon per os administration, in line with oral treatment of neurodevelopmental disorders. Notably, ARN23746 does not present signs of toxicity or diuresis even if administered up to 50 times the effective dose. These results further support ARN23746 as a solid candidate for clinical trial-enabling studies.

22 Jul 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Bertozzi, Sine Mandrup ; Contestabile, Andrea ; Ottonello, Giuliana ; Manigrasso, Jacopo ; Savardi, Annalisa ; Borgogno, Marco ; Portioli, Corinne ; Armirotti, Andrea ; Turci, Alessandra ; Cancedda, Laura ; De Vivo, Marco

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.

01 Aug 2020·ChemQ1 · CHEMISTRY

Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders

Q1 · CHEMISTRY

Article

Author: Summa, Maria ; Cancedda, Laura ; Bertorelli, Rosalia ; Ortega, Jose Antonio ; Savardi, Annalisa ; La Sala, Giuseppina ; Armirotti, Andrea ; Contestabile, Andrea ; De Vivo, Marco ; Borgogno, Marco ; Narducci, Roberto

Aberrant expression ratio of Cl^- transporters, NKCC1 and KCC2, is implicated in several brain conditions. NKCC1 inhibition by the FDA-approved diuretic drug, bumetanide, rescues core symptoms in rodent models and/or clinical trials with patients. However, bumetanide has a strong diuretic effect due to inhibition of the kidney Cl^- transporter NKCC2, creating critical drug compliance issues and health concerns. Here, we report the discovery of a new chemical class of selective NKCC1 inhibitors and the lead drug candidate ARN23746. ARN23746 restores the physiological intracellular Cl^- in murine Down syndrome neuronal cultures, has excellent solubility and metabolic stability, and displays no issues with off-target activity in vitro. ARN23746 recovers core symptoms in mouse models of Down syndrome and autism, with no diuretic effect, nor overt toxicity upon chronic treatment in adulthood. ARN23746 is ready for advanced preclinical/manufacturing studies toward the first sustainable therapeutics for the neurological conditions characterized by impaired Cl^- homeostasis.

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Indication	Highest Phase	Country/Location	Organization	Date
Down Syndrome	Preclinical	Italy	Istituto Italiano di Tecnologia	01 Aug 2020

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