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

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• 作者：Igor Shamovsky ; Stephen Connolly ; Laurent David ; Svetlana Ivanova ; Bo Nord&#xe9 ; n ; Brian Springthorpe ; Klaus Urbahns
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 13, 2008
• 年：2008
• 卷：51
• 期：5
• 页码：1162 - 1178
• 全文大小：3165K
• 年卷期：v.51,no.5(March 13, 2008)
• ISSN：1520-4804

文摘

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, pIC₅₀^CCR − LogD. Fragment-based QSAR analysis is performed using the lipophilicity-adjusted hERG potency, pIC₅₀^hERG − LogD, 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.