Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower plasma LH, and it displayed the best off-target safety profile that led to its clinical candidate nomination for the treatment of sex-hormone disorders.
Keywords: FSH; GnRH; LH; NK3 antagonist; neurokinin B; triazolopiperazine.