Shamovsky Igor, Connolly Stephen, David Laurent, Ivanova Svetlana, Nordén Bo, Springthorpe Brian, Urbahns Klaus
Department of Medicinal Chemistry, AstraZeneca R&D Lund, S-22187 Lund, Sweden.
J Med Chem. 2008 Mar 13;51(5):1162-78. doi: 10.1021/jm070543k. Epub 2008 Feb 8.
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.
非心血管药物对hERG通道的抑制是一种严重阻碍新药物研发的副作用。为提高临床前化合物对hERG的选择性，我们建议使用基线亲脂性关系方法研究与预期靶点和hERG的非去溶剂化相关相互作用。虽然这种方法传统上用于效能研究，但我们在此证明它有助于解决选择性问题。对四类内部趋化因子受体（CCR）拮抗剂进行的hERG选择性研究表明，通过增加亲脂性调整后的主要效能pIC 50（CCR）-Log D的结构改变，选择性得到最有效的提高。使用亲脂性调整后的hERG效能pIC 50（hERG）-Log D进行基于片段的定量构效关系分析，以识别与hERG通道形成非疏水相互作用的部分。然后可以避免这些会削弱hERG选择性的部分。一种新颖的基于二维片段的定量构效关系分析有助于直观呈现化学系列中亲脂性调整后的hERG和CCR效能。
