Desired Compounds Consultation

Subject 

Request for Help

We're looking to identify a new set of compounds for the next round of optimisation. This is happening in addition to sourcing of commercially available analogues that will fill a bit more of the SAR space but aren't necessarily exactly what we want.

We've posted a list of compounds on OpenWetWare that contains a range of the things were after, along with a SMARTS filter summary.  We've had feedback and ideas submitted before here on TSL and some of those ideas have been included in this list. Below I've posted the 10 "priority" compounds from the list. It's very much open to debate so get involved. Once we've had a bit of feedback, we'll settle on a definitive list and go after them by any means necessary. The plan was to mostly concentrate on the side-chain, leaving the aryl pyrrole unit mostly untouched for the moment.

 

[Edit 0905 AEST 15 June 2012: Added letter identifiers for compounds to aid discussion.]

Desired Compounds Consultation Phase 2

Subject 

Request for Help

The evaluation of the arylpyrroles has gone well, in that we've identified promising new antimalarial compounds. Besides their high potency, they exhibit high levels of activity in a late-stage gametocyte assay which is very exciting. (As an open source project, anyone may take these results and work on them - made easy by all our data being available.) It's for these reasons of potency that we're going to explore one more iteration of the series, despite three of the compounds showing no oral activity in mice. It's thought the problem could be low solubility. This round will only be including compounds with low (<5) logP, and we'd like to play around with the structure a little more.

If this round does not throw out any improved compounds we'll probably park the series. Hence it's important that we choose a good set of compounds to evaluate. We decided to list the top 10 "most wanted" compounds that we could access commercially, as well as a similar list of compounds we could not buy and wanted to make. We'd then attempt to source those commercial compounds, and ask the synthesis community to volunteer to make the other necessary compounds.

We're now assembling the lists. We'd compiled a first-pass list of attractive compounds. We've now modified that list to give two new lists of commercial vs. synthetic compounds - below. We now need to consult the community again on these new lists. Before embarking on synthesis or purchase we will have the compounds checked by the original authors of the GSK TCAMS set to see whether any of the compounds have been evaluated and found to be inactive - we'll send the SMILES of all these compounds to GSK and see what they say. We know that's a big ask.

First the compounds we'd like to get our hands on which are commercially-available:

If any of these are known by GSK, we'll fill up the spaces with compounds from these backups, or any others people might like to see tested:
 

The compounds we'd like to evaluate which are not commercially-available are:

(note that primary, secondary and tertiary terminal amides are all of interest here and ought to be made concurrently.

And again, these are the backups in case these compounds have already been evaluated:

In the synthesis set:

1) We've included a couple of pyrazoles. Fused pyrazoles quite different to the GSK hit compounds are commercially-available, and we've not included those because of the substantial differences - those options are shown here, and we could include some if needed.
2) We've taken the curveballs out as being a little speculative, but if anyone knows how to make these, or wants to have a go, please say.
3) We've de-prioritised the thiazolidinones as being too insoluble, even with some obvious tweaks. This means we have three slots available for the synthesis "top 10 most-wanted." Our final phase of consultation will be to fill those slots.

The final consultation will hopefully be a public hangout on the web for a final discussion, technology permitting. Date to be advised. This will finish the "Most Wanted" lists and begin the next phase of compound evaluation. So this is where we stand - would anyone do this differently?

On a side note, that will probably need a post of its own, the logPs in the above are approximate. We've been using available tools to calculate these, e.g. Chemdraw, but there's a lot of variability depending on the tool used. We have no access here to one that performs well, from ACDLabs. While it's likely the above figures are inaccurate (vs. truth) it's unlikely they are so far out as to invalidate a target).
 

Consultation Outcome

Subject 

Results

Firstly, thanks for coming to the online meeting. I found it worked quite well (minor glitches aside) but it would be great to hear your thoughts. We'll post the recording up in the near-ish future. The OpenWetWare wiki will soon be updated to reflect the outcomes of the meeting, along with SMILES. Of course if anyone is keen and beats me to it, then even better.

The discussion focused really on the selection of synthetic compounds. The list of commercial compounds (below) remained the same. The project is now looking for willing donors (ca. 5 mg) for these compounds. 

 

The list of synthetic compounds saw some changes. Partially because some of the original list have already been made. The replacements were discussed and found for these and the blank spaces were filled. These compounds look to mitigate the problems observed with the previous rounds of testing. Please let us know if these structures aren't what you were expecting to see here. The two compounds highlighted in blue are one's that are currently receiving attention here at Sydney. 

Final top 10 synthetic targets

 

The project now needs synthetic teams to investigate the other targets. Any groups looking for academic collaboration or industrial contributions would be gratefully received. It could potentially be a good way for a CRO to showcase their expertise in turning out compounds. We would be willing to provide starting material if necessary.