Physicochem metabolism PK
The scheme below shows all the inherited met/PK data inherited, plus additional data for compounds more recently sent to Monash (green). (Associated discussion: GHI 107). Dec 2016: Tool for predicting sites of metabolism
For the more recent set, solubility was still seen as low and needs improving. The metabolic stability measured for the recent set appears not to be a mouse-specific event and needs to be improved to deliver a candidate. Met ID data (below) could help in the design of new analogs with improved stability. Is there a correlation between metabolic stability and Log D?
Some inherited data where the nature of the assay used was not clear: MMV669360 CLint 142 uL/min/kg and t1/2 = 12 min.
The PK curve for the relatively weak amide MMV670246 is shown below for oral & IV legs & parameters. The original data are contained in this picture.
A compound with better in vitro balance is MMV670652 but this compound has not been in rat PK. It may be possible to improve potency by synthesis of the more potent enantiomer - this is being addressed through synthesis of the synthetically simpler methyl analog OSM-S-208, the enantioenriched version of which was MMV669844.
The data for MMV639565 were contained in an inherited PDF summary of pharmacokinetics and efficacy.
As would be expected HLM ''vs.'' RLM shows a general correlation with approx 4-fold shift on average. However, for most of the more potent analogs, this increases to over 10-fold. The figure below shows the 4 sub 30 nM compounds with HLM & RLM measured: MMV670652, MMV670945, MMV670438 and MMV670947. (It looks like there are several other compounds here exhibiting good metabolic parameters for which we do not have data)
