Development of a Highly Potent Neurokinin-3 Receptor Inhibitor: Design, Synthesis, and Evaluation

The neurokinin-3 receptor (NK3R) has emerged as a promising therapeutic target. Recent evidence indicates that oral administration of an NK3R antagonist to block neurokinin B signaling significantly alleviates hot flash symptoms. Despite this potential, only one NK3R ligand (ESN-364) has been clinically approved to date. To address this gap, we developed a series of imidazolepiperazine derivatives (13a–13l, 17a–17f, and 22a–22i) through rational design and synthesis. Molecular docking validated the structural rationale, with compound 22i demonstrating superior target binding potency and robust NK3R inhibitory activity. Notably, 22i exhibited an enhanced membrane permeability and high oral bioavailability. In vivo efficacy studies revealed that oral 22i effectively suppressed luteinizing hormone levels, supporting its potential for further optimization.