Exciting times: First in vivo submissions

10 Apr
Published by pylioja


Request for Help

It's exciting as usual on the project. We've submitted the three compounds for in-vivo oral evaluation in a mouse model. The original hits TCMDC-123812 and -123794 were submitted along with one of Zoe's near neighbours, ZYH 3-1. It's not the most active of our compounds with an IC50 of 26 nM, but its logP comes in at just under 5 or there abouts (see: http://www.thesynapticleap.org/node/384#comment-798). It's still pretty high so we'll see how it goes. Courtesy of MMV, we also just had the chance to put TCMDC-123812 and ZYH 3-1 in for a hERG assay at 11 and 33 μM. As for the mode of action, Mat already mentioned some in silico prediction work by Iain Wallace and GSK is now following up one of these potential targets.
structures of TCMDC-123794, TCMDC-123812 and ZYH 3-1
On the synthesis front, the ether and amine linkers are still on the cards but the reductive amination isn't playing ball at the moment (PMY 38-* e.g. PMY 38-4) I've also just started to address the lipophilic heterocycle on the near neighbour set and looking for ester-isosteres on the -123* series (PMY 45-1, PMY 46-1).

Zoe has now finished her summer project so I'm back on my own on these two series here at Sydney so more synthetic hands on the bench would be useful. We've also drawn up a list of target compounds for the that we're hoping to source by whatever means necessary, please feel free to add to it as it isn't an exhaustive list yet. The key here is to identify nice analogues with better physical properties. With the near neighbour compounds our main concern is the thiozolidinone moiety. Although it looks quite polar at a first glance, it's essentially a lump of grease. The "Michael-acceptor" is not very reactive at all. It tolerates an excess of NaBH4 (PMY 39-1). Upon treatment with benzylthiol the compound is stable until the addtion of base allows some kind of reaction but not the expected conjugate addition (PMY 41-1). It would be nice to dump on a nice polar group to help bring the logP down, we haven't explored the effect of the 2-imino component, so this might be a nice place to start.

I also thought it would be interesting to start looking at the effect of the pyrrole unit, so I've started another series featuring a pyrazole. The synthesis of the core has been facile so far so it can be classed as "low hanging fruit" for us to pick. The guys at CDRI are moving forward with further near-neighbour analogues and are keen to work with the pyrazole sub-series