Synthesis and Evaluation of a Novel Zuranolone Analog with High GABA Receptor PAM Activity and Excellent Pharmacokinetic Profiles.

Zuranolone (SAGE-217), the first FDA-approved oral neurosteroid (NAS), a positive allosteric modulator (PAM) of γ-aminobutyric acid type A (GABA) receptor for postpartum depression approved in 2023, has limitations such as short half-life, low bioavailability, and central inhibitory side effects. To address these, we designed novel C-21 modified derivatives of Zuranolone, identifying the triazolone scaffold as key for enhancing GABA activity. Here, we synthesized Zuranolone analogs with diverse triazolone substituents, finding that pyridine-derived modifications improved the activity correlated with LogP. The optimal derivative, (2-(trifluoroethoxy)pyridine-triazolone, LogP 4.61), showed 2.5-fold greater potency (EC) and efficacy (Emax) than Zuranolone (LogP 4.78) at synaptic/extrasynaptic GABA receptors, attributed to stronger binding via molecular docking. In rats, exhibited 5-fold longer plasma T, 6-fold higher AUC, 3-fold greater brain exposure, and 30% improved bioavailability. It also outperformed Zuranolone in pentylenetetrazole (PTZ)-induced seizure suppression and threshold dose for loss of righting reflex (LORR) in rats. The C21-pyridine-triazolone pharmacophore in enhances receptor activity potency without increasing lipophilicity, optimizing pharmacokinetics and safety, which makes it a promising therapeutic candidate for depression and epilepsy.