Synthesis and evaluation of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues as histamine-3 receptor antagonists

Bioorg Med Chem Lett. 2012 Jan 1;22(1):186-9. doi: 10.1016/j.bmcl.2011.11.038. Epub 2011 Nov 16.

Abstract

A novel class of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship identified sulfone 27 with excellent H(3)R affinities in both humans and rats, and acceptable pharmacokinetic properties. Further, compound 28 achieved single digit nanomolar H(3)R affinities in both species with minimum hERG activity.

MeSH terms

  • Animals
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Drug Interactions
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Histamine Antagonists / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Liver / metabolism
  • Mice
  • Models, Chemical
  • Piperidines / chemistry*
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Histamine Antagonists
  • KCNH2 protein, human
  • Piperidines
  • Receptors, Histamine H3
  • Spiro Compounds