Inhibitory effect of carboxylic acid group on hERG binding.
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.
Zhu
Bing-Yan
BY
Portola Pharmaceuticals, Inc., 270 East Grand Ave., Suite 22, South San Francisco, CA 94080, USA. bzhu@gene.com
Jia
Zhaozhong J
ZJ
Zhang
Penglie
P
Su
Ting
T
Huang
Wenrong
W
Goldman
Erick
E
Tumas
Daniel
D
Kadambi
Vic
V
Eddy
Priya
P
Sinha
Uma
U
Scarborough
Robert M
RM
Song
Yonghong
Y
D001550:Benzamidines / Q000378:metabolism*; D002264:Carboxylic Acids / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D006801:Humans
D001550:Benzamidines; D002264:Carboxylic Acids; D051638:Ether-A-Go-Go Potassium Channels; D065427:Factor Xa Inhibitors; C032157:benzamidine