The GSK Aminothienopyrimidine (ATP) Series

Subject 

Results

The second strand of the open source drug discovery for malaria project involves aminothienopyrimidines (ATPs). The wiki summary page contains the current To Do list. Child pages to this one refer to specific aspects of the project.

Biological Data

Subject 

Results

Chid pages to this one focus on biological evaluation in the GSK ATP project - results and the response to the results.

 

Biological Results for ATP Series from April 2013

Subject 

Results

Comments on Latest Biological Results - April 2013

Data may be viewed here.
General page for the whole aminothienopyrmidine series is here.

The content of this post is also viewable on a Google+ post.

The results of the first major round of synthesis and evaluation for the aminothienopyrimidines are in, following a preliminary round that validated the GSK hit, as well as an exploration of the commercial space around the hit. The design of the latest round was carried out with the following principles in mind:

1) Creating a set of structures with considerable diversity, given that the hit, OSM-S-106, arose from a phenotypic screen so has no known target/mechanism of action.
2) Maintaining low calculated logP values, and being mindful of molecular weight.
3) Exploring whether the sulfonamide (and its meta position) is necessary. This was to some extent guided by which boronic acids/esters could be bought/made.
4) Exploring whether the amine on the pyrimidine could be substituted. A morpholine at this position was seen as being a sensible variation because of this modeling analysis. The longer side chain employed in e.g. OSM-S-137 was proposed because of mild activity for TCMDC 132385 (comparison of structures).
5) Given the quality of the hit OSM-S-106, this compound has been resynthesised and we will approach Sue Charman's lab for some solubility and basic metabolic stability assays. There is always the chance that the first hit will be the best compound.

The data show that essentially all changes did not just lead to a reduction in potency, but obliteration of activity. This is surprising. In several cases there appeared to be some sort of solubility issues, though we had expected all these compounds to be highly soluble.

It would be useful to hear the thoughts of medicinal chemists reading this, in terms of what these data suggest. It would seem as though the meta sulfonamide is very necessary for some activity, and that the morpholine is not a good substituent to pursue. Results for OSM-S-137 vs TCMDC 132385 (structures here) suggest that variation of amine is possible where there is some variation (i.e. removal) in the sulfonamide portion and this raises the possibility that we might be looking at two targets - one hit by the substituted pyrimidine and one by the aryl sulfonamide.

The project needs suggestions about what to make in the next round. Please comment below, either with your name or anonymously. The gut feelings of people with some experience of this stage of drug discovery would be very valuable.

In addition, if you happen to have in stock some thienopyrimidines that you feel might be worth evaluating, and you'd be willing to send to a local lab for biological evaluation, please say so below. Accessing relevant compounds is something the project is not doing enough of, partly because we don't yet have a Molecular Craigslist.

Short term plans:

1. Morpholine group appears to be a bad substitution. Make other substitutions on the primary amine, such as one or two methyls (dimethyl InChIKey CGTVWFYTOADSRO-UHFFFAOYSA-N). Route to that would likely be to take OSM-S-70, add dimethylamine, then brominate, then Suzuki. Action item for Althea.
2. How many more meta-substituted sulfonamides like OSM-S-106 exist in the literature? We've done this search before (link?), but let's revisit. Action item for Alice.
3. We already ordered several other meta-substituted boronic acids (link?), some of which have now come in. We need to evaluate these. Action item on Althea.
4. Are there any doubly-substituted meta-boronic acids we could employ in the coupling? Action item on Alice.
5. TCMDC-132385 should be synthesised to check its activity, as well as the fragments without the fluoroaromatic, and with other aryls. Action item on Murray.
6. Ask GSK for any information they might have on known inactives around OSM-S-106 where there is variation in that pendant amine side chain. Action item on Mat.
7. Make OSM-S-106 with substitution of the amine with a methyl ether (InChIKey RMRWXSBDYMDPPE-UHFFFAOYSA-N). Devise synthetic approach. Action item on Alice.
8. Approach Sue Charman's lab for solubility and metabolic assays on OSM-S-106. Action item on Mat.

Longer term plans are:

1. Synthesise des-amino OSM-S-106 (NAPAWLMTRGMNSY-UHFFFAOYSA-N), i.e. substitute the amine for H on the pyrimidine. Who?
2. Can OSM-S-106 be derivatised further, i.e. this compound as a starting point? Who?
3. Can Murray's new bromo-regioisomer synthesis be used to make more diverse compounds. How risky is this in terms of the amount of methodology needed? Who?
4. How easily can scaffold analogs of OSM-S-106 be accessed, e.g. furan (GSJDJXHDXORRDD-UHFFFAOYSA-N), flipped thiophene (NBFDNDWQCGJNHN-UHFFFAOYSA-N), pyrrole (XTMBLMGMAYOFBP-UHFFFAOYSA-N), indole (ZVHBDXVFFFLUQY-UHFFFAOYSA-N), pyridine vs pyrimidine (FCEYCXXGTFVWIS-UHFFFAOYSA-N)? Any takers for synthesis?