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Inhibitory effect of carboxylic acid group on hERG binding.

Abstract：

:Drug-induced QT prolongation arising from drugs' blocking of hERG channel activity presents significant challenges in drug development. Many, but not all, of our benzamidine-containing factor Xa inhibitors were found to have high hERG binding propensity. However, incorporation of a carboxylic acid group into these benzamidine molecules generally leads to hERG inactive compounds regardless where the carboxyl group is tethered within the molecules. The inhibitory effect of a carboxylic acid group on hERG binding has also been observed in many series of diverse structural scaffolds (including non-amidines). These findings suggest that the negatively charged carboxylate group causes unfavorable interaction within hERG channel binding cavity by electrostatic interaction.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Zhu BY,Jia ZJ,Zhang P,Su T,Huang W,Goldman E,Tumas D,Kadambi V,Eddy P,Sinha U,Scarborough RM,Song Y

doi

10.1016/j.bmcl.2006.08.039

subject

Has Abstract

pub_date

2006-11-01 00:00:00

pages

5507-12

issue

21

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(06)00936-X

journal_volume

16

pub_type

杂志文章

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