Piperazinotriazole-based NK3R antagonists: Rational design, synthesis, and identification of an orally active lead...

The neurokinin-3 receptor (NK3R) has emerged as a promising non-hormonal therapeutic target for menopausal hot flashes, with fezolinetant being the only clinically approved NK3R antagonist to date. To overcome this therapeutic limitation, we designed a series of imidazolepiperazine derivatives (17a-17c, 21, 23a-23u), among which 23i(R) demonstrated superior pharmacological properties including potent NK3R inhibition (IC₅₀ = 65.42 ± 6.54 nM), strong target binding (IC₅₀ = 53.61 ± 3.67 nM), excellent membrane permeability (Papp A-B = 27.3 × 10^-6 cm/s; ER = 0.53), and remarkable oral bioavailability (165 %). In ovariectomized rat models, 23i(R) effectively suppressed luteinizing hormone levels while exhibiting favorable pharmacokinetics and tolerability, establishing it as a promising clinical candidate for further development as a next-generation NK3R antagonist.