Druggability of the Arylpyrrole leads (TCMDC-123794 etc)

Published by MatTodd on 27 August 2011 - 12:25pm

Project is starting with a couple of leads from the GSK Tres Cantos set. There is a newly-published analysis of the druggability of the compounds in the original data set. The arylpyrrole series is listed as one of the most promising (though the Aryl-F is missing in the published paper - presume that is a clerical error).
Tres Cantos are appealing for collaborators to work with them on these compounds, which is an excellent idea. That's what we're doing, except that the project hosted here is open source, meaning anyone can see what we're doing and guide the direction of the project.
The initial phase is the resynthesis of these leads and their validation. We will soon be moving to analog synthesis. The obvious first question for the community of medicinal chemists is: what should we change?
My gut feeling was to verify the need for the aryl-F and the methyls on the pyrrole. Paul Willis' gut feeling was that ester. Gut feelings and half-formed thoughts enormously welcome as comments below.


Going back to my med chem days here are a few comments
1)The 4-fluoro is usually incorporated in order to prevent para-hydroxylation which can happen all too readily. As the fluoro is well tolerated in terms of space and lipophilicity, then removal doesn't make much sense. If you want something MORE lipohilic there (if there is some binding pocket) then you can stick in a chlorine or trifluoromethyl. You have to be a bit cautious with the latter,though, as significant plasma protein binding can occur when the molecule gets in vivo (though you should be OK given the lipophilicity of your starting compound).
2) Agreed that the main in vivo concern would be the ester linkage. If it is just a linkage, then you should just be able to stick in an aliphatic chain (or better an ether to prevent benzylic oxidation).
3) As for the dimethyl, this has to be a "suck it and see" if there are no analogues to compare with. 

MatTodd's picture

Bill - des-F (for the sake of it) and Ar-Me analogs happening here. CF3 is one we'd like to do. I think the removal of the ester is going to the next thing, after Paul's completed the synthesis of the lead. The requirement of the ester is actually synthetically annoying, so there's another reason to get rid of it.
Listed some near neighbours here, but not gone through to extract bioactivity data yet.