From HTS to Market: the Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 193

Activity against the hERG channel was not unexpected, as the original lead
(1) had significant activity and also because the chemotype conforms to generic
descriptors predicting hERG activity. 39 Other companies have subsequently
reported hERG activity for their CCR5 analogues, including Schering 40 and
Merck. 41 Docking 9 into a model of the hERG ion channel suggested that
adding polarity around the amide or the benzimidazole ring could reduce
hERG anity (Figure 9.5). 42,43 Having said that, the SAR for hERG activity is
often highly subtle, and the ability to rapidly generate SAR within the series of
interest is of greater value than a generic pharmacophore-based model. A high-
throughput hERG binding assay was used to generate this SAR. 44
Introduction of polarity around the amide bond was the synthetically most
accessible option, and a wide number of polar-containing analogues were
prepared in parallel. Within this dataset of analogues, it became clear that the
endo isomer was preferred. A number of key (endo) analogues are shown in
Table 9.3.
Significant changes in overall polarity (as measured by log D) were not
necessary to modulate hERG activity; careful placement of polar groups in the
amide substituent could dramatically reduce ion channel activity. This
empirical SAR identified compounds that retained good antiviral activity
whilst exhibiting essentially no hERG activity, including 14 and 15, although
Figure 9.5 General pharmacophore for hERG (blue balls highlight regions requiring
lipophilicity) overlaid onto a model of 9 (purple) docked into the K 1
channel binding pocket (grey surface) and protein structure (green helices).