A quantitative assessment of hERG liability as a function of lipophilicity.
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.
Waring
Michael J
MJ
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. mike.j.waring@astrazeneca.com
Johnstone
Craig
C
D000465:Algorithms; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016208:Databases, Factual; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D016015:Logistic Models; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008055:Lipids; D026902:Potassium Channel Blockers