Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor.

The neurokinin-3 receptor (NK3R) is one of three receptors that recognize neurokinins. The finding that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist can significantly improve hot flash symptoms independent of any hormonal effect fits strongly suggest that NK3R is a viable drug target and that drugs targeting this receptor could be novel pharmacotherapies. Currently no NK3R ligands have been approved for the treatment of human disorders. Herein, we designed and synthesized a series of novel imidazolepiperazine derivatives (16a-16x, 20a-20f, 29a-29m) and performed molecular docking to confirm the design, among which the target compound 16x exhibited promising inhibitory activity against NK3R (IC = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound for further optimization and development.