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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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