hERG, Gametocytes, Metabolism, In Vivo

15 May
Published by pylioja



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 hERGgametocytemetabolism 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.  


cdsouthan's picture

Paul, firstly what was the positive control antimalarial compound used in the mouse study ?  Secondly, if you can pick up OSM-S-35 and others in that series as decent RP-HPLC peaks you could certainly do some simple mouse plasma solubility and stability studies at your end as a prelude to sending candidates off for in vivo work.

The study was commissioned by MMV and carried out at Swiss TPH using their methods. I guess a comment from them would be more suitable here? From the data, it looks like the study was carried out relative to a untreated, infected mouse rather than a positive to control.
It would be interesting to have some plasma stability/solubility studies carried out. We don't really have the facility in our department but the Charman lab at Monash would. The original metabolism study was carried out on a number of compounds (not OSM-S-35 but analogues) and the solubility was calculated in phosphate buffer but not in plasma. The issue at the moment is whether it's worth doing that, or whether we ought to be dealing with the solubility issue? What do you think?

cdsouthan's picture

As we know the solubility parameters constrain (and can confound) all the biology experiments.  It should thus go at the top of the triage and be done rigourously.

Agreed. My feeling is that sourcing a few near neighbour analogoues that are more soluble (some desired compounds shown here) would still help us answer if this is a good point to move away from the near neighbours or not. If a more soluble version maintains the activity, then its probably worth looking a little deeper. If not then maybe best move on. We have plenty of options to explore if one series doesn't look great and of course others are free to pick up where we left off on anything.