N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

Bioorg Med Chem Lett. 2006 Nov 15;16(22):5752-6. doi: 10.1016/j.bmcl.2006.08.085. Epub 2006 Sep 6.

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

  • Administration, Oral
  • Animals
  • CHO Cells
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Fluorine / chemistry*
  • Fluorine / pharmacology
  • Hydrazines / chemistry*
  • Hydrazines / pharmacology
  • Neurotransmitter Agents / pharmacology*
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Quinolines / chemistry*
  • Quinolines / pharmacology
  • Receptors, Neurokinin-3 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Hydrazines
  • N-((methoxycarbonyl)(phenyl)amino)-3-(4-tert-butylpiperazin-1-ylmethyl)-8-fluoro-2-phenylquinoline-4-carboxamide
  • Neurotransmitter Agents
  • Piperazines
  • Quinolines
  • Receptors, Neurokinin-3
  • Fluorine
  • carbohydrazide