N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

Article abstract of DOI:10.1016/j.bmcl.2006.08.085

Introduction of selected amine containing side chains into the 3-position of N′,2-diphenylquinoline-4-carbohydrazide based NK₃ antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI_Kr affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ₉₀ 7 mg/kg po; plasma Occ₉₀ 0.4 μM) and has good selectivity and excellent PK properties.