Novel 3-phenylpiperidine-4-carboxamides as highly potent and orally long-acting neurokinin-1 receptor antagonists with reduced CYP3A induction

Bioorg Med Chem. 2012 Jan 15;20(2):962-77. doi: 10.1016/j.bmc.2011.11.048. Epub 2011 Dec 1.

Abstract

The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK(1) receptor antagonists. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24h after oral administration. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.

MeSH terms

  • Administration, Oral
  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / pharmacology*
  • Animals
  • Cytochrome P-450 CYP3A / metabolism*
  • Enzyme Activation / drug effects
  • Guinea Pigs
  • Humans
  • Microsomes / metabolism
  • Motor Activity / drug effects
  • Neurokinin-1 Receptor Antagonists*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Pregnane X Receptor
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Steroid / metabolism
  • Stereoisomerism

Substances

  • 1-(amino(oxo)acetyl)-N-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide
  • Amides
  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Pregnane X Receptor
  • Receptors, Neurokinin-1
  • Receptors, Steroid
  • Cytochrome P-450 CYP3A