31 Jul
Published by pylioja



Previously, we found that we had no efficacy for the compounds tested in our  in vivo plasmodium berghei study. Until now we haven't had our pharmacokinetic to figure out why this was. We had previously found that OSM-S-5 (PMY 10-6/TCMDC-123812) is rapidly metabolised in mouse plasma, but that it is stable in human plasma. The PK data we have just obtained (Thanks MMV!) shows that within 1 hour, a 50 mg/kg dose results in about a 2 μM plasma concentration of the compound. However within 4 hours, the concentration is down to less than the 3D7 IC50 of the compound. I think this is fairly good evidence for the reason this compound failed in vivo. It also confirms that it's a good idea for the project to continue to investigate less metabolically labile side-chains for the series. It's good news that we're at least getting decent plasma concentration from oral delivery.


This is a good beginning.  I suppose going further, it should be possible to study in vivo PK and efficacy for compounds having higher solubility and lower metabolic liability.   Both factors could ensure that the pharmacodynamics (PD, at this point unknown?) are obtained for efficacy.  ThePD could be: high enough Cmax / IC50 (max plasma concentration relative to IC50), high enough AUC/ IC50 (exposures relative to IC50, Area under conc time curve) or time / IC50.  

Absolutely. The third round is hoping to address issue of metabolic stability. If these compounds give decent in vitro results then they'll certainly be progressed and be subjected to more detailed PK if investigated in vivo. Fingers crossed for decent potency in the new compounds!