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 (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.
Gentles
Robert G
RG
Research and Development, Bristol Myers Squibb Co., 5 Research Parkway, Wallingford, CT, USA. robert.gentles@bms.com
Hu
Shuanghua
S
Huang
Yazhong
Y
Grant-Young
Katherine
K
Poss
Michael A
MA
Andres
Charles
C
Fiedler
Tracey
T
Knox
Ronald
R
Lodge
Nicholas
N
Weaver
C David
CD
Harden
David G
DG
D001030:Apamin / Q000737:chemistry*; D001667:Binding, Competitive; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D026902:Potassium Channel Blockers / Q000737:chemistry*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D020033:Protein Isoforms; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013793:Thallium / Q000737:chemistry
D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D020033:Protein Isoforms; D011720:Pyrazoles; D011743:Pyrimidines; D001030:Apamin; D013793:Thallium; C030986:pyrimidine