Synthesis and biological evaluation of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives for T-type calcium channel blockers

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5910-5. doi: 10.1016/j.bmcl.2011.07.087. Epub 2011 Jul 29.

Abstract

To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 4-piperidinecarboxylate and 4-piperidinecyanide derivatives were prepared and evaluated for in vitro and in vivo activity against α(1G) calcium channel. Among them, several compounds showed good T-type calcium channel inhibitory activity and minimal off-target activity over hERG channel (% inhibition at 10 μM=61.85-71.99, hERG channel IC(50)=1.57 ± 0.14-4.98 ± 0.36 μM). Selected compound 31a was evaluated on SNL model of neuropathic pain and showed inhibitory effect on mechanical allodynia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channel Blockers / chemical synthesis*
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / metabolism
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, T-Type / metabolism*
  • Disease Models, Animal
  • Drug Design
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • HEK293 Cells
  • Humans
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / physiopathology
  • Inhibitory Concentration 50
  • Ligands
  • Mibefradil / metabolism
  • Molecular Structure
  • Molecular Targeted Therapy
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology
  • Patch-Clamp Techniques
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Quantitative Structure-Activity Relationship
  • Rats
  • Spinal Nerves / surgery
  • Structure-Activity Relationship

Substances

  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Ether-A-Go-Go Potassium Channels
  • KCNH1 protein, human
  • Ligands
  • Piperidines
  • Mibefradil