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

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 co

SUBMITTER: Savardi A 

PROVIDER: S-EPMC7427514 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature