Preliminary SAR studies on non-apamin-displacing 4-(aminomethylaryl)pyrrazolopyrimidine K(Ca) channel blockers

An exploratory SAR study on a series of potent, non-apamin-displacing 4-(aminomethylaryl)pyrazolopyrimidine K(Ca) channel blockers is described and their selectivity against K(Ca) channel subtypes is reported. The most potent analog, 5-chloro-N-(thiophen-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 18; no. 20; p. 5694
Main Authors Gentles, Robert G, Hu, Shuanghua, Huang, Yazhong, Grant-Young, Katherine, Poss, Michael A, Andres, Charles, Fiedler, Tracey, Knox, Ronald, Lodge, Nicholas, Weaver, C David, Harden, David G
Format Journal Article
LanguageEnglish
Published England 15.10.2008
Subjects
Apamin - chemistry
Binding, Competitive
Cell Line
Electrophysiology
Humans
Inhibitory Concentration 50
Models, Chemical
Potassium Channel Blockers - chemistry
Potassium Channels, Calcium-Activated - metabolism
Protein Isoforms
Pyrazoles - chemical synthesis
Pyrazoles - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Structure-Activity Relationship
Thallium - chemistry
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Summary:An exploratory SAR study on a series of potent, non-apamin-displacing 4-(aminomethylaryl)pyrazolopyrimidine K(Ca) channel blockers is described and their selectivity against K(Ca) channel subtypes is reported. The most potent analog, 5-chloro-N-(thiophen-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (24) displayed sub-micromolar activity in both a thallium flux and whole-cell electrophysiology assay and did not displace apamin in a competitive binding study.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2008.08.026