Synthesis and SAR of 4-aminocyclopentapyrrolidines as N-type Ca²⁺ channel blockers with analgesic activity

Bioorg Med Chem. 2012 Jul 1;20(13):4128-39. doi: 10.1016/j.bmc.2012.04.057. Epub 2012 May 4.

Abstract

A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacology
  • Acetamides / therapeutic use
  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Behavior, Animal / drug effects
  • Calcium Channel Blockers / chemical synthesis*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use
  • Calcium Channels, N-Type / chemistry*
  • Calcium Channels, N-Type / metabolism
  • Disease Models, Animal
  • Male
  • Pain / drug therapy
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • 2,2-dicyclohexyl-N-(2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta(c)pyrrol-4-yl)acetamide
  • Acetamides
  • Analgesics
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Pyrrolidines
  • pyrrolidine