Discovery of a novel series of selective HCN1 blockers

Identification of some selective and potent HCN1 blockers is described. The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-09, Vol.21 (18), p.5197-5201
Main Authors: McClure, Kelly J., Maher, Michael, Wu, Nancy, Chaplan, Sandra R., Eckert, William A., Lee, Dong H., Wickenden, Alan D., Hermann, Michelle, Allison, Brett, Hawryluk, Natalie, Breitenbucher, J. Guy, Grice, Cheryl A.
Format: Article
Language:English
Subjects:
Analgesic
Analgesics
Animals
benzamides
Biological and medical sciences
Bradycardia
chemical inhibitors
Cyclic Nucleotide-Gated Cation Channels - antagonists & inhibitors
Cyclic Nucleotide-Gated Cation Channels - metabolism
Drug Discovery
HCN1
HCN4
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Indans - chemical synthesis
Indans - chemistry
Indans - pharmacology
Ion channel
ion channels
Medical sciences
Mice
Molecular Structure
Neuropathic pain
Neuropharmacology
Pharmacology. Drug treatments
Potassium Channels - metabolism
Spared nerve injury model
Stereoisomerism
Strecker reaction
Structure-Activity Relationship
VIPR assay
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Summary:Identification of some selective and potent HCN1 blockers is described. The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.07.051