Known Near Neighbours of Initial Tres Cantos Leads

We're starting with the resynthesis of two leads from the GSK Tres Cantos dataset. The obvious question is: are there other, related structures in the dataset that might give us information on what to change next?

 

Paul Willis from MMV did a quick "near neighbour" search (25 Aug 2011), particularly with an eye to getting rid of the ester in the lead structures. Structures below. As he said: "The first compound is a ketone analogue of the ester lineage – it's a singleton and not an ideal group from a drug discovery perspective but indicates other groups may be tolerated.  The next set is the entire cluster output of another near neighbor I spotted – all have replacements for the ester group (again not especially drug like but possible indication that wide variation possible at this position) and interestingly some contain variations on the 4-F-Ph"

 

Cc1ccc(cc1)n2c(cc(c2C)C(=O)CN3C(=O)C(NC3=O)Cc4ccccc4)C
Cc1cc(c(n1c2ccc(cc2)Cl)C)C=C3C(=O)N(C(=Nc4ccccc4)S3)C5CCCC5
Cc1ccnc(c1)n2c(cc(c2C)C=C3C(=O)N(C(=Nc4ccccc4)S3)Cc5ccco5)C
Cc1cc(cc(c1)n2c(cc(c2C)C=C3C(=O)NC(=Nc4ccc(cc4)Cl)S3)C)C
CCOC(=O)c1ccc(cc1)n2c(cc(c2C)C=C3C(=O)N(C(=Nc4ccccc4)S3)C5CCCC5)C
CCn1c(cc(c1C)C=C2C(=O)NC(=Nc3ccccc3)S2)C

 

Questions:

 

1) Are there other structures that are "similar" in the GSK set - searchable at Chembl.

2) What do these structures tell us about what to change next in the lead compounds?

3) Importantly, can we gain access to analogous structures that have been evaluated but not reported?

Interestingly this includes compounds that are related to the TC hits above but which were perhaps assayed against other targets.

Data for the above compounds will be posted to the wiki page. Discussion of them can more easily happen in comments below.

Synthesis Strategy for Near Neighbours

The evaluation of a synthesis strategy toward "near neighbours" of the TCMDC-123812 and -123794 is underway. Current efforts summarised as shown below:
Near Neighbour Synthesis
The experimental details are outlined in experiments PMY 13-1, PMY 14-1 and PMY 16-1. The synthesis appears straightforward but the final hydrolysis step resulted in material that was contaminated by grease (presumably from lab glassware). I'll update when I've repeated the reaction, while avoiding introduction of grease!