Overcoming Undesirable hERG Potency of Chemokine Receptor Antagonists Using Baseline Lipophilicity Relationships

Abstract

The inhibition of the hERG channel by noncardiovascular drugs is a side effect that severely impedes the development of new medications. To increase hERG selectivity of preclinical compounds, we recommend the study of nondesolvation related interactions with the intended target and hERG using a baseline lipophilicity relationship approach. While this approach is conventionally used in studies of potency, we demonstrate here that it can help in selectivity issues. Studies of hERG selectivity in four in-house classes of chemokine receptor (CCR) antagonists suggest that the selectivity is improved most effectively by structural alterations that increase the lipophilicity-adjusted primary potency, pIC 50 (CCR) - Log D. Fragment-based QSAR analysis is performed using the lipophilicity-adjusted hERG potency, pIC 50 (hERG) - Log D, to identify moieties that form nonhydrophobic interactions with the hERG channel. These moieties, which erode hERG selectivity, can then be avoided. A novel two-dimensional fragment-based QSAR analysis helps visualizing the lipophilicity-adjusted hERG and CCR potencies within chemical series.

Global Analysis of Small Molecule Binding to Related Protein Targets

“…Medicinal chemistry experience shows that the addition of a single methyl group to the structure of a lead compound can change binding affinity by one order of magnitude [38]–[41]. Classically, this paradigm is associated with the small molecule part of a binding interaction as the ligand is amenable to chemical modification.…”

Chemokine Receptors as Targets for Cancer Therapy

“…Sudden cardiac death arising from an arrhythmia (Torsade de Pointes) is a known issue in drug development because a large number of drugs with features of lipophilic amines show unintended inhibition of the human ether-à-go-go related gene (hERG), which encodes a potassium ion channel protein [120]. Because small molecule CKR antagonists often contain a basic amine in order to interact with a glutamic acid residue present in the seventh transmembrane domain of CKRs, this structural feature may also lead to non-selective inhibition of hERG, thus increasing the risk of arrhythmia in a small group of patients.…”

“…Reproduced with permission from Rockefeller Press [43]. vanced strategies to measure and avoid nonhydrophobic interactions of CKR antagonists with the hERG channel can help select agents with decreased risk of cardiac complications [120,121]. Fig.…”

Should Cardiosafety be Ruled by hERG Inhibition? Early Testing Scenarios and Integrated Risk Assessment

“…If such a reduction is not possible, or is accomplished but hERG activity still remains, they caution that specific structural modification is necessary. Shamovsky et al [94] demonstrated the use of lipophilicity-adjusted hERG potency to reduce hERG liability in a chemokine receptor antagonist project.…”