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.

Cl ^-转运蛋白 NKCC1 和 KCC2 的异常表达率与几种大脑状况有关。FDA 批准的利尿剂布美他尼对 NKCC1 的抑制可挽救啮齿动物模型和/或患者临床试验的核心症状。然而，由于抑制肾脏 Cl ^-转运蛋白 NKCC2 ，布美他尼具有强烈的利尿作用，造成严重的药物依从性问题和健康问题。在这里，我们报告了一种新化学类别的选择性 NKCC1 抑制剂和主要候选药物 ARN23746 的发现。ARN23746在鼠唐氏综合症神经元培养物中恢复生理细胞内 Cl ^-，具有出色的溶解性和代谢稳定性，并且在体外没有显示脱靶活性问题. ARN23746 可恢复唐氏综合征和自闭症小鼠模型的核心症状，无利尿作用，成年后长期治疗也无明显毒性。ARN23746 已准备好进行高级临床前/制造研究，以针对以 Cl ^-体内平衡受损为特征的神经系统疾病的首个可持续疗法。