hERG Activity
MMV669844 and MMV670944 (OSM-S-175) were evaluated in a hERG assay, with the data indicating issues with both compounds that will need to be addressed. To investigate whether this is a problem for the series, several compounds (inherited and new, attempting to reduce cLogP - GH Issue #211) were evaluated for activity by AstraZeneca using this assay to see if this activity can be reduced. The results suggest that either the pendant OCHF2 or the amide is a problem. In contrast the previous two data points suggest that hERG activity can be obtained with compounds containing neither feature. Future analogs will need to address this. Cumulative data shown below (from here and here).
A further 9 compounds have been screened for hERG activity, including the lead compound from Series 3 and one molecule from the Open Source Mycetoma project:
Discussion of next set for evaluation (Dec 2018)
Former OSM postdoc Murray Robertson is applying literature hERG pharmacophore models to the series (GH Issue #188), and a community appeal is active for a laboratory willing to run higher-throughput binding assays (GH Issue #192). There is a lot of literature on hERG models (i.e. how to reduce hERG activity) with the most recent being an analysis of the ChEMBL database concluding that the dominant influence remains lipophilicity. A cryoEM structure has been published by Rod Mackinnon.