Consultation Outcome

Published by pylioja on 26 July 2012 - 6:59am

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.

 

Comments

cdsouthan's picture

Paul, I'd be please to take the short list of 20 round the databases again. When you update the Wiki with the SMILES  you might want to check that chemicalize.org will convert the page OK.  I also suggest you do belt and braces by including IUPAC and InChI (strings and keys). You might also want to formaly enumerate the synthetic proposals to explicit sets (i,e, for the R and amide permutations).   I can check and send  the PubMed CIDs for the ones on order.  You might also give some more thought to your internal (and now de facto global)  naming system and ID strings to reduce ambiguity (B < sB?).  I guess when the virtuals become real you can give a three-digit PMY numbers (re-number old ones before it gets too crowded?)   and when the purchases turn up.    If you add the InChI key under your image displays that locks them down as well.
(BTW I am still regularly getting new password requests).
 

The naming system used above (cB, sB etc) is just temporary and only for the purposes of discussion. Once the compounds are made/received and become real, they'll receive the OSM- number and of course the batch number (e.g. PMY-XX-X or whatever supplier batch number they have). You're right about the formalising the R groups for ID purposes, but we are interested in pretty much any group there for the moment so we wanted the diagram to reflect that. As always, thanks.

The OpenWetWare wiki has been updated with the InChi's and smiles for the synthetic and commercial compounds.

cdsouthan's picture

Paul, I wonder if you could re-surface on OpenWetWare an updated but very brief summary of, say, the current top-ten actives (including any TCAMS re-tests) with their average activity.   The reason for asking is that more open sources of patent-extracted structures have popped up recently
http://cdsouthan.blogspot.se/2012/08/pubchem-pips-9-million-patent-extra...
It could thus now be useful to take these leads for another walk through the databases.
If you could specify specify structures with the usual belt-and-braces IUPACs SMILES and InChIs, this makes for easy chemicalization and database checking.

MatTodd's picture

...can be found here: http://www.youtube.com/watch?v=ooM8kuo14Bg

 

Still (Aug 21 2012) really searching for CROs or other labs who might be interested in making one or two of these compounds. An update on that in the next comment.

MatTodd's picture

Status of the compounds needing synthesis (August 21st 2012)

sA - Matin Dean, a student in Sydney, has started to look at this compound

sB - Paul Ylioja is working on this one (but is travelling now until the end of September)

sC - Sanjay Batra from CDRI Lucknow has said he'll make one of these compounds. All data will go online

sD - Nobody currently on this, though Paul had a few goes, e.g. here

sE - Needed - nobody working on

sF - Needed - nobody working on

sG - Being worked on by Paul and a Sydney undergrad student Matt Tarnowski Lab book

sH - Needed - nobody working on

sI - Sanjay is going to take this one - lab notebook coming

sJ - Sanjay will take this one too - lab notebook coming

 

News on the commercial compounds soon - ready to order, just clearing a few last hurdles.

Dear Matt,
Nice to learn of  the eforts you are putting in.Who picksup the tabs for the synthesis of these devlopments?
Regards
Murzban.

MatTodd's picture

Hi Murzban,

We're looking for people to make the compounds for zero charge. The compounds are not complex. Because this is an open project, all data need to be shared, and this acts as an excellent advertisment for a company's synthetic abilities. There would also be co-authorship on a paper. For other reasons why industry might participate in a project like this see this previous comment.

Alice Williamson's picture

Following so far unsuccessful attempts to synthesise Sd (post on its way!) I have decided to start focusing on compounds of type Sh. I just need to decide which heterocycle(s) to tether to the pyrrole 3-position.

I have been thinking about heterocycles that would allow us to systematically develop the subsituent at this position position to effect more favourable in vivo results. The first row of compounds feature 1 heteroatom, the second row 2 heteroatoms and the third two nitrogen heteroatoms which would provide a handle for further derivitisation of the final compounds.

Does anyone have any thoughts regarding which compound(s) I should target first?

 

MatTodd's picture

These all look to be good options to me. I'd keep it simple, and what you're doing now seems perfectly reasonable.I like the thiazolidinone, but for no rational reason.

MatTodd's picture

Jonathan Baell commented to me offline. To paraphrase. As a general rule an Sp3 S joined to a carbonyl always comes with higher risk of metabolic instability so we should probably go for the others first. The same holds for a thioether (more likely oxidation than hydrolysis in this case) but that there are always exceptions so this shouldn’t be seen as black and white.

MatTodd's picture

The list as of October 4th:

(sA - Matin Dean has synthesised this compound).

sB - Paul Ylioja is nearly there.

sC - Sanjay Batra from CDRI Lucknow has said he'll make one of these compounds, but this one is still needed. People are asking which amino acids should be incorporated. The short answer is: at this stage, who cares? The long answer is: rac-alanine would be fine, but this can be changed to your favourite amino acid.

sD - In progress. Paul had a few goes, e.g. here. Alice has had many attempts at this compound now, and it's proving to be a pain, e.g. here. Alice will post a summary...

sE - Matin is having a go at this one, e.g. here.

sF - Still needed - nobody working on

sG - Being worked on by Paul and a Sydney undergrad student Matt Tarnowski Lab book A version is also being worked on by one of the CDRI students, e.g. here.

sH - Alice is now taking a pop at this, e.g. here.

sI - Sanjay wanted to take this one, but nobody currently working on it.

sJ - Sanjay wanted this one too, but nobody working on it since last update. Paul wants to make it, like this.

 

We've put in a quote request to both Assay Depot and Science Exchange, and are receiving inputs/quotes for a few of these molecules, which might be a way to go if we don't get any takers. I summarised the reasons why CROs might want to get involved in this part of the project here.

 

 

MatTodd's picture

...and the oxadiazole, incidentally, does not have to be as shown. When I spoke with Ed Tate recently he extolled the virtues of the "symmetrical" 1,3,4-isomer, which would be absolutely fine. Lots of nice precedence for synthesis, obviously.

Really looking forward with interest to the results of some of these, especially Si and Sj to move away from the pyrrole. btw nice review on oxdiazoles in JMC vol 55 (2012) 1817-1830.

MatTodd's picture

An update on where we are with finishing off the arylpyrrole set of compounds. The aim is to complete the synthesis of the 10 Most Wanted compounds above and have them biologically evaluated. The commercial compounds have been ordered from Molport and are on their way to us - arrival due Monday 22nd October if customs clearance goes well, at which point they will be re-vialled and bounced to Vicky Avery's lab at Eskitis.

sA - Done. Sent for testing already.
sB - Nearly there - Paul is confirming identity.
sC - To do. It may be prudent to wait for the evaluation of the related tertiary amide from the commercial set before worrying about the synthesis of more complex variants, but this is a judgement call.
sD - Need - despite our best efforts this compound is proving to be a pain. I wonder if this could benefit from CRO input?
sE - Matin is working on this - he's just tried the penultimate step, a chlorination. If that's worked, coupling with an amine should be easy.
sF - Alice is working on one oxadiazole isomer, and John Wallis has indicated he might be interested in the other.
sG - Matt Tarnowski has been working on this molecule, but the end of semester is rapidly approaching. We reckon he can do it, but just in case, Murray (who's joined the project) is going to bring some material through so we can play with coupling conditions.
sH - Alice is on this set and has nearly finished purifying several.
sI - Nobody on this yet. We've had some interest from a CRO who have quoted us a price for making a few milligrams. The exact heterocyclic ring is not terribly important though. Maybe there are other possibilities. Murray and Alice are thinking this over. Alice was wondering about making a triazole via a click.
sJ - Paul says he's made this, and is acquiring the final characterization today.

Sanjay Batra's lab have been making a methyl isomer of one of the pyrazoles which will be a useful addition.

This is the state of play. If you're reading this, and want to take part by making a molecule, you can. Our next meeting is this Friday (Oct 19th) at about 4:30 pm Sydney time. Link coming for those who want to join in.

 

We have been short of chemicals required for the desired synthesis and have therefore indented some of them. In the meantime Harikrishna is trying to standardize the synthesis using analogous compounds. The schemes for the synthesi of SJ and SI are being uploaded here.
For SJ, hydrolysis step is yet not complete. We have adopted this route as we did not have bromoacetamide in the lab.
For SI a tentative scheme is drawn and the synthesis is to be initiated.

Alice Williamson's picture

Hello Sanjay,

The route for SI looks good. However we have already synthesised and submitted the two pyrazoles shown below and found them to be inactive, so I don't think its so important to pursue this compound. What does everyone else think? Would be great to get SI though!

Alice