HERG inhibition

Correlations between the HERG chaimel inhibition and GRIND descriptors were analyzed using multivariate techniques such as principal component analysis (PCA) and PLS regression analysis. 

In order to assess the importance of the presence of a charged nitrogen atom, the dataset was divided into two subsets. The first subset contained 338 compounds without any basic nitrogen atoms while the second set consisted of 544 molecules with one or two basic nitrogen atoms. 

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Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

Subsequent efforts focused on reducing hERG inhibition. This goal was successfully accomplished using the triazole moiety instead of benzimidazole in... 

Figure 3.5 Pl< profile of a compound with hERC inhibition with an IC50 between 20-30 XM. The effective plasma concentration is 10 xM. The single dose produced a spike of over 30 xM plasma concentration, not required for therapeutic effect but for a sufficient level 12 hours after administration. However, the associated with this dose/formulation reached the level when hERG inhibition occurs.

The giga-Ohm seals achieved by the PatchXpress (Molecular Devices) [60, 61] and QPatch (Sophion Biosciences) [62] make them the higher-throughput patch clamp instruments of choice for hERG inhibition screening as they are more comparable... 

Figure 16.4 shows the chemical structures of a variety of molecules with potent activity against the hERG channel, including withdrawn drugs and Class III antiarrhythmics. Below are some examples of different structures associated with hERG inhibition. 

In our experience, it is crucial for a project team to be aware of hERG inhibition as the main LQT risk factor during the early phases of drug discovery and to have easy access to training materials and internal experts if consultation is needed. During lead selection, use of appropriate hERG assays and early LQT risk assessments must be done in the context of a lead series represented by at least ten compounds (Figure 16.5). 

Prior to beginning development, many sponsors would also have conducted in vitro safety pharmacology studies (e.g., hERG inhibition) to assess cardiovascular concerns, as well as single-dose and 5- to 7-day repeated-dose non-GLP-compliant studies to assess toxicity and help set doses for the GLP-compliant studies (see Table 7.3). 

The Admensa Interactive tool developed by scientists from Inpharmatica incorporates several ADME properties, namely log P, log Dy 4 (log P at pH 7.4), aqueous solubility, human intestinal absorption, BBB penetration, cytochrome P450 (CYP) affinities, P-glycoprotein transport, hERG inhibition and PPB to score and prioritize their molecules. 

While most reports in the literature employ a modified version of Lipinski s Rule-of-Five criteria, a few have used models that are more sophisticated as part of the design. Many QSAR models have been reported in the literature for many different ADMET related properties, from solubility to permeability to hERG inhibition to metabolic stability. Several recent... 

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