Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders
Annalisa Savardi, Marco Borgogno, Roberto Narducci, Giuseppina La Sala, Jose Antonio Ortega, Maria Summa, Andrea Armirotti, Rosalia Bertorelli, Andrea Contestabile, Marco De Vivo, Laura Cancedda, Annalisa Savardi, Marco Borgogno, Roberto Narducci, Giuseppina La Sala, Jose Antonio Ortega, Maria Summa, Andrea Armirotti, Rosalia Bertorelli, Andrea Contestabile, Marco De Vivo, Laura Cancedda
Abstract
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.
Keywords: Down syndrome; GABAergic transmission; KCC2; NKCC1; NKCC2; autism; brain disorders; chloride homeostasis; drug discovery; small molecule.
Conflict of interest statement
A.C. and L.C. are named as co-inventors on the following granted patent: US 9,822,368; EP 3083959; JP 6490077; A.C. and L.C. are named as co-inventors on the patent application WO 2018/189225. A.S., M.B., J.A.O., A.C., M.D.V., and L.C. are named as co-inventors on patent application IT 102019000004929.
© 2020 The Authors.
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