NDI-5033

**NDI-5033** is a small molecule activator of adenosine monophosphate-activated protein kinase (AMPK) developed by NephroDI Therapeutics for nephrogenic diabetes insipidus (NDI), particularly the congenital X-linked form caused by mutations in the vasopressin type-2 receptor (V2R). By phosphorylating aquaporin-2, it enhances water reabsorption in the kidney, increasing urine osmolality by 30-50% in preclinical models of NDI (tolvaptan-treated rats and V2R knockout mice) without inducing hypoglycemia, unlike metformin. Administered orally with high bioavailability (>85%), it shows sustained efficacy over 3 weeks and no tachyphylaxis, positioning it as a promising therapy for this orphan pediatric condition affecting 1 in 250,000 males, where current management relies on burdensome hydration and diets that risk complications like kidney damage.