Proper intracellular Cl concentration is fundamental for physiological brain development and function. Accordingly, the aberrant expression of Cl importer NKCC1 and/or exporter KCC2 is implicated in several brain conditions, including autism spectrum disorders (ASD), Down syndrome (DS), and drug-resistant epilepsy (DRE). Interestingly, NKCC1 inhibition rescues core symptoms of these brain conditions in rodent models and/or clinical trials. However, current NKCC1 inhibitors have diuretic effects by also inhibiting the kidney Cl transporter NKCC2. These diuretic effects pose critical health concerns, strongly jeopardizing current unselective NKCC1 inhibitors from becoming a viable therapy for long-term chronic treatments. To overcome these issues, we discovered and developed a new class of selective NKCC1 inhibitors, which were effective in rescuing core brain-related symptoms in animal models of idiopathic autism and DS without showing any diuretic and toxic effects. Our lead drug-candidate IAMA-6 is currently being evaluated in a first-in-human Phase 1 clinical study for its safety and pharmacokinetic profile in healthy volunteers. Here, we report the efficacy of IAMA-6 in ameliorating behavioral and cognitive deficits in a mouse model of Fragile X, a genetic and syndromic form of ASD, and in reducing seizure frequency in a model of DRE. We found that chronic treatment with IAMA-6 rescued social behaviors and memory deficits in Fragile X mice and reduced hippocampal discharges in mice with DRE. These new results confirm IAMA-6 as an effective treatment for neurological conditions characterized by an altered Cl homeostasis and further increase the number of therapeutic indications that may benefit from IAMA-6 treatment.