The Frontrunners

[alintheopen]

For discussion - the content of this thread is included in the wiki, but discussion can take place here:

The following actives (MMV670246 is poorly active but included for comparison) have been identified as the "frontrunners" for further exploration by OSM. All but one of these compounds were found to be active in a whole cell assay, but only one has been tested in Kiaran Kirk's ion regulation assay.

A large range of data has been measured for the compounds and this is captured below in a condensed form of the master chemical list.

*note please feel free to provide comments on this data - the key green for good, yellow for OK and red for poor has been employed for a quick guide to assist when glancing over the data.

In order to further probe the MoA of the series four compounds it is necessary to send these compounds for testing by the Kirk group at ANU. For example, three of the compounds have been tested in vivo and are able to kill the parasite in mice, but the MoA is still to be tested. We would also like to fill in the gaps in the data where possible as this will help when rationalising compound design and also for assembly of the S4 paper.

The active compounds are mainly ethers along with a few amides and one amine.)

Ethers
MMV663915 highly active, still to be tested in ion regulation assay.
MMV670936 active with good cytotox and hERG profile, still to be tested in ion regulation assay.
MMV639565 highly active in whole cell and in vivo, still to be tested in ion regulation assay.

Chiral ethers of particular interest owing to activity and the ability to explore/compare both enantiomers for each compound:
MMV669844 highly active in whole cell and in vivo, still to be tested in ion regulation assay. Problematic hERG profile.
MMV672687 good activity and cLogP but no further data yet.
MMV688896 good activity and cLogP but no further data yet.
MMV670652 highly activity, some clearance data but need to gather more.
MMV670437 highly active, cLogP on target and basic amine centre is of interest for further exploration.

Amides
MMV670246 was found to be a weakly hit in the ion regulation assay and to possess low activity in the whole cell assay. Hence, further data should be collected.
MMV670767 is an amide with good whole cell activity but we should collect more data.
MMV670944 is an active amide with lots of data - ion regulation data is required in order to produce a complete profile for the paper.

Amine
MMV669848 active in the Kirk assay and has shown other promising properties, more exploration required.

Resynthesis is required in order to provide adequate quantities of the compounds for testing.

New Compounds
We have shipped 12 compounds for potency evaluation and are awaiting data before folding the compounds into this issue.
However, one existing compound MMV670947 has shown good activity and either this or the newly synthesised MMV693155 should be sent for testing.

We also need to look at some inactive/weakly active compounds and examine them in the Kirk assay and collect other data (hERG, Cytotox, clearance etc.). Some suggestions are:

Pyridine ethers
MMV688895 - this compound should be re-tested in whole cell to confirm a lower potency than MMV670936 and also tested in the Kirk assay.

Amides
MMV675947 and MMV675946 are moderately active amides that would serve as good controls in Kirk assay.
MMV675718 is an inactive amide that should be included as a negative control in Kirk assay.

[mattodd]

Great. As per IVIVC conversation (#389) two of the three suggestions I made for in vivo clearance work are in the above list (MMV670944 and MMV669844), but the original amide suggestion of MMV668958 could be replaced with the above, MMV670767, which is a similar compound in terms of potency and clearance.

[mattodd]

Requirements for late lead (mentioned in meeting #386), according to MMV website:
i) potency <100 nM,
ii) ideally solubility *>100uM* (40 microg/mL if assume MW ca. 400)
iii) ideally efficacy ED90 <10mg/Kg.

As short term goals we need:
iv) better rodent half life (say t1/2 >150 minutes) or show the current issues are rodent specific and have this in a cpd with potency <100 nM so we can go back into the model.

We thus need to acquire the relevant data on targeted frontrunners to validate them, or not.

[edwintse]

Of the compounds listed above, I should be able to easily resynthesise the following 7 compounds as we've got the SM's on hand. The compounds in the box are also easy but will require purchasing of the amine SM's.

[edwintse]

Resynthesis commencing. ELN entries: here

[mattodd]

Good stuff, Ed - as you start to make these can you check them off the above and update us if you complete syntheses? It'd be good if we can clarify to people which compounds remain to be made in as near to real time as we can.

[alintheopen]

Ed and I have been working hard to resynthesise the Frontrunners and we are nearly there...hope to be sending compounds to ANU in the next week or so and also a large batch to Syngene (including @edwintse's beautiful cubanes etc.)
This set of compounds will be the test set for #417
Here is an update of our progress. Green - ready, orange = close, red = a little further away.

[MFernflower]

Slightly unrelated but I was wondering if you could dehydrate mmv669848
with DDQ in-order to produce an isoindole? As for reduction of the parent
amide - perhaps try NaBH4? @alintheopen

[alintheopen]

UPDATE 310816

[MFernflower]

@alintheopen @edwintse is the molecule in blue going to be shipped off for testing?

[alintheopen]

UPDATE 200916

Trying to fix up the amine as per issue #435

[MFernflower]

Alice, unrelated question but what drawing package do you use?

[alintheopen]

Hi @MFernflower I use ChemDraw.
Oh and in answer to your earlier question, we are going to send EGT 111-1 too :)

[MFernflower]

Would it be possible to compile a list of molecules that were sent out and are waiting for results?

[alintheopen]

It is and we will do, but we are currently finishing off the amber compounds. This will come when we send them :)

[edwintse]

UPDATE 311016

Compounds MMV672687 and MMV670437 are shown in the original post above with a CN in the 4-position of the NE aromatic ring. Racemic versions of these compounds were successfully synthesised (right 2 compounds below), however it has occurred to us that these compounds DO NOT actually correspond to the MMV numbers below the compounds. The actual compounds contain the OCHF2 group in the 4-position (left 2 compounds below)

We are currently working to synthesise racemic versions of the correct compounds and will update again when completed.

[edwintse]

Potency data has been obtained and has been written up here.

[MFernflower]

@edwintse This is awesome news! looks like my methoxy idea worked and so did the cubane LHS replacement! Wondering if we should try other cage hydrocarbons along the lines of something like this? http://www.sigmaaldrich.com/catalog/product/aldrich/340367?lang=en&region=US