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Inhibitory effect of carboxylic acid group on hERG binding.
Bing-Yan Zhu1, Zhaozhong J Jia, Penglie Zhang
1Portola Pharmaceuticals, Inc., 270 East Grand Ave., Suite 22, South San Francisco, CA 94080, USA. bzhu@gene.com
Bioorganic & Medicinal Chemistry Letters
|August 26, 2006
Summary
Incorporating a carboxylic acid group into drug candidates, like factor Xa inhibitors, can prevent hERG channel binding and reduce the risk of QT prolongation, a common drug development challenge.
Area of Science:
- Pharmacology
- Cardiovascular Science
- Medicinal Chemistry
Background:
- Drug-induced QT prolongation is a major hurdle in pharmaceutical development, often linked to inhibition of the human ether-à-go-go-related gene (hERG) channel.
- Benzamidine-containing factor Xa inhibitors have shown potential but frequently exhibit high hERG binding, posing safety concerns.
Purpose of the Study:
- To investigate the impact of incorporating a carboxylic acid group on the hERG binding propensity of benzamidine-based factor Xa inhibitors.
- To elucidate the mechanism by which carboxylic acid groups influence hERG channel interactions.
Main Methods:
- Synthesis and electrophysiological assessment of benzamidine-containing factor Xa inhibitors with and without carboxylic acid modifications.
- Comparative analysis of hERG channel binding affinity across diverse structural scaffolds.
Main Results:
- Many benzamidine-containing factor Xa inhibitors displayed significant hERG binding.
- Introduction of a carboxylic acid group consistently abolished hERG binding, irrespective of its position in the molecule.
- This inhibitory effect was observed across various chemical structures, not limited to benzamidines.
Conclusions:
- The negatively charged carboxylate group appears to induce unfavorable electrostatic interactions within the hERG channel binding cavity.
- Strategic incorporation of carboxylic acid moieties represents a viable approach to mitigate hERG-related safety liabilities in drug design.
- This finding has broad implications for developing safer drug candidates across different therapeutic areas.
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