A quantitative assessment of hERG liability as a function of lipophilicity

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1759-64. doi: 10.1016/j.bmcl.2006.12.061. Epub 2006 Dec 22.

Abstract

The impact of lipophilicity as a factor contributing to hERG potency is assessed for a large dataset of compounds of differing ionisation type. This dataset is derived from compounds tested in the IonWorks-based in vitro electrophysiology hERG assay at AstraZeneca. Using logistic regression, a quantification of the risk associated with increasing lipophilicity is presented. The anticipated differences between acidic, basic and neutral compounds are apparent in the data but lipophilicity is shown to be a stronger driver for hERG potency than might have been expected. Simple rules defining target lipophilicity values for minimizing hERG liability are derived.

MeSH terms

  • Algorithms
  • Chemical Phenomena
  • Chemistry, Physical
  • Databases, Factual
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / drug effects*
  • Humans
  • Lipids / chemistry*
  • Logistic Models
  • Potassium Channel Blockers / chemistry*
  • Potassium Channel Blockers / pharmacology*

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Lipids
  • Potassium Channel Blockers