Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists

Bioorg Med Chem Lett. 2010 May 1;20(9):2755-60. doi: 10.1016/j.bmcl.2010.03.071. Epub 2010 Mar 20.

Abstract

Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.

MeSH terms

  • Administration, Oral
  • Animals
  • Azepines / chemical synthesis
  • Azepines / chemistry*
  • Azepines / pharmacokinetics
  • Brain / metabolism
  • Dogs
  • Drug Evaluation, Preclinical
  • Histamine H3 Antagonists / chemical synthesis
  • Histamine H3 Antagonists / chemistry*
  • Histamine H3 Antagonists / pharmacokinetics
  • Humans
  • Mice
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacokinetics
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Receptors, Histamine H3 / metabolism
  • Structure-Activity Relationship

Substances

  • 1-(2-(4-cyclobutyl-(1,4)diazepane-1-carbonyl)-4-(3-fluorophenoxy)pyrrolidin-1-yl)ethanone
  • Azepines
  • Histamine H3 Antagonists
  • Pyrrolidines
  • Receptors, Histamine H3