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.
MeSH terms
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Administration, Oral
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Animals
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CHO Cells
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Cricetinae
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Dose-Response Relationship, Drug
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Fluorine / chemistry*
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Fluorine / pharmacology
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Hydrazines / chemistry*
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Hydrazines / pharmacology
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Neurotransmitter Agents / pharmacology*
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Piperazines / chemistry*
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Piperazines / pharmacology
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Quinolines / chemistry*
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Quinolines / pharmacology
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Receptors, Neurokinin-3 / antagonists & inhibitors*
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Hydrazines
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N-((methoxycarbonyl)(phenyl)amino)-3-(4-tert-butylpiperazin-1-ylmethyl)-8-fluoro-2-phenylquinoline-4-carboxamide
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Neurotransmitter Agents
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Piperazines
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Quinolines
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Receptors, Neurokinin-3
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Fluorine
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carbohydrazide