Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5757-5764. doi: 10.1016/j.bmcl.2016.10.049. Epub 2016 Oct 17.

Abstract

Herein, we report the synthesis and structure-activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4 receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.

Keywords: Addiction; Difluoropiperidine; Dopamine 4 receptor; PD-LIDs; Selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology*
  • Crystallography, X-Ray
  • Dopamine Antagonists / chemistry*
  • Dopamine Antagonists / pharmacology*
  • Drug Discovery
  • Halogenation
  • Humans
  • Isomerism
  • Models, Molecular
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Rats
  • Receptors, Dopamine D4 / antagonists & inhibitors*
  • Receptors, Dopamine D4 / chemistry
  • Receptors, Dopamine D4 / metabolism

Substances

  • Antipsychotic Agents
  • Dopamine Antagonists
  • Piperidines
  • Receptors, Dopamine D4