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hERG, Gametocytes, Metabolism, In Vivo
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I've been on holiday for a couple of weeks and it's nice to come back to a whole load of biological data. Before I left I submitted compounds for hERG, gametocyte, metabolism and in vivo mouse assays. Mat has already posted up the results of these here on synaptic leap and I've just posted the in vivo mouse data. Mat has also written a nice summary of the project so far on OpenWetWare. All of this data is exciting and puts us into the position of having to make some hard choices about where to go next.
The in vivo mouse model (P. Berghei) did not show any efficacy for our compounds. The trial was terminated after 4 days when infected mice did not show a decrease in their parasitized red blood cell count. This is a problem of course but I'm not disheartened yet as the solubility of the near neighbour compound OSM-S-35 is very low and was quite unlikely to achieve oral efficacy first time round. The original GSK hits TCMDC-123812 and TCMDC-123794 (OSM-S-5 and -6 respectively) have sensible logD values but, as shown by the metabolism study, only moderate metabolic stability. We expected this and are looking at ester isosteres to avoid the probably hydrolysis of this bond. What we don't yet know is why the mouse trial unsuccessful and we're hoping pharmacokinetic data will help us answer this question. The good news about the compounds are that they are hERG clear and most interestingly at the moment, that the near neighbours show excellent activity in the gametocyte assay.