ABSTRACT
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 (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.
Subject(s)
Fluorine/chemistry , Hydrazines/chemistry , Neurotransmitter Agents/pharmacology , Piperazines/chemistry , Quinolines/chemistry , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Fluorine/pharmacology , Hydrazines/pharmacology , Piperazines/pharmacology , Quinolines/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.
Subject(s)
Hydrazines/chemistry , Hydrazines/pharmacology , Neurotransmitter Agents/chemistry , Neurotransmitter Agents/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
