SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of GnRH secretion and has also been implicated in the generation of hot flashes. Therefore decreases of LH and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism.To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men.Randomized, placebo-controlled, double-blind, single ascending dose study.Phase 1 unit.Seven cohorts of 6 healthy men 18-45 years (4:2 randomization to SJX-653/placebo per cohort).single oral doses of 0.5 to 90 mg SJX-653.Safety assessments and serial Pharmacokinetic (PK)/PD measurements.SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5h independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70±7% (mean±sd) at 6h after 30 mg SJX-653, versus 10±43% for placebo (p = 0.0006); maximal T reduction was of 68±5% at 8h after 60 mg SJX-653, versus 18±11% for placebo (p < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL.These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.