title: 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.
authors.affiliation: Portola Pharmaceuticals, Inc., 270 East Grand Ave., Suite 22, South San Francisco, CA 94080, USA. bzhu@gene.com
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
authors.forename: Zhaozhong J
authors.initials: ZJ
authors.lastname: Jia
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Su
authors.forename: Wenrong
authors.initials: W
authors.lastname: Huang
authors.forename: Erick
authors.initials: E
authors.lastname: Goldman
authors.forename: Daniel
authors.initials: D
authors.lastname: Tumas
authors.forename: Vic
authors.initials: V
authors.lastname: Kadambi
authors.forename: Priya
authors.initials: P
authors.lastname: Eddy
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Song
mesh_terms: 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
chemical_list: D001550:Benzamidines; D002264:Carboxylic Acids; D051638:Ether-A-Go-Go Potassium Channels; D065427:Factor Xa Inhibitors; C032157:benzamidine