Urgent: List of Compounds to Send for hERG Assay

[mattodd]

We can in the very short term get 5-10 compounds tested for hERG. We need a list in the next 24 hours @alintheopen @tscmacdonald @JoannaUbels

Background discussion at last meeting is here: http://malaria.ourexperiment.org/osddmalaria_meeting_/9470 hERG data that has precipitated this more in-depth look: http://malaria.ourexperiment.org/biological_data/9562

The compounds can be inherited ones or new ones we have made.

Inherited: taken from the sheet with the most up-to-date quantities in it (http://malaria.ourexperiment.org/biological_data/10041 - but no drawn structures, just codes, so for the moment correlate with structures in the wiki http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series) but we should ideally use the compounds with the most amounts remaining since these are likely still to have amounts available.

New: we need that list up @alintheopen #210

Unless good reason not to, suggest 3-5 inherited, 3-5 synthesised. Meaning maybe 3 new amides, 3 new ethers, then 3 older compounds? Non-potent and potent OK, so we don't have to wait for data back on the samples posted to GSK.

Guidelines: The compounds should span a range of pKa (for the amines), Log D and it would be good to look at 1°,2° and 3° amines if we had them. Amounts we need: 1-2 mg. Suggestions please, but Sydney people let's get together Wed to talk.

[newgitontheblock]

What time do you want to meet? Will get submitted list up after starting a couple of reactions.

On 20 May 2014, at 10:57 pm, Mat Todd notifications@github.com wrote:

We can in the very short term get 5-10 compounds tested for hERG. We need a list in the next 24 hours @alintheopen @tscmacdonald @JoannaUbels

Background discussion at last meeting is here: http://malaria.ourexperiment.org/osddmalaria_meeting_/9470 hERG data that has precipitated this more in-depth look: http://malaria.ourexperiment.org/biological_data/9562

The compounds can be inherited ones or new ones we have made.

Inherited: taken from the sheet with the most up-to-date quantities in it (http://malaria.ourexperiment.org/biological_data/10041 - but no drawn structures, just codes, so for the moment correlate with structures in the wiki http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series) but we should ideally use the compounds with the most amounts remaining since these are likely still to have amounts available.

New: we need that list up @alintheopen #210

Unless good reason not to, suggest 3-5 inherited, 3-5 synthesised. Meaning maybe 3 new amides, 3 new ethers, then 3 older compounds? Non-potent and potent OK, so we don't have to wait for data back on the samples posted to GSK.

Guidelines: The compounds should span a range of pKa (for the amines), Log D and it would be good to look at 1°,2° and 3° amines if we had them. Amounts we need: 1-2 mg. Suggestions please, but Sydney people let's get together Wed to talk.

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[alintheopen]

Sorry that's me replying from wrong email.

On Wednesday, May 21, 2014, newgitontheblock notifications@github.com wrote:

What time do you want to meet? Will get submitted list up after starting a couple of reactions.

On 20 May 2014, at 10:57 pm, Mat Todd notifications@github.com<javascript:_e(%7B%7D,'cvml','notifications@github.com');> wrote:

We can in the very short term get 5-10 compounds tested for hERG. We need a list in the next 24 hours @alintheopen @tscmacdonald @JoannaUbels

Background discussion at last meeting is here: http://malaria.ourexperiment.org/osddmalaria_meeting_/9470 hERG data that has precipitated this more in-depth look: http://malaria.ourexperiment.org/biological_data/9562

The compounds can be inherited ones or new ones we have made.

Inherited: taken from the sheet with the most up-to-date quantities in it (http://malaria.ourexperiment.org/biological_data/10041 - but no drawn structures, just codes, so for the moment correlate with structures in the wiki http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series) but we should ideally use the compounds with the most amounts remaining since these are likely still to have amounts available.

New: we need that list up @alintheopen #210

Unless good reason not to, suggest 3-5 inherited, 3-5 synthesised. Meaning maybe 3 new amides, 3 new ethers, then 3 older compounds? Non-potent and potent OK, so we don't have to wait for data back on the samples posted to GSK.

Guidelines: The compounds should span a range of pKa (for the amines), Log D and it would be good to look at 1°,2° and 3° amines if we had them. Amounts we need: 1-2 mg. Suggestions please, but Sydney people let's get together Wed to talk.

— Reply to this email directly or view it on GitHub.

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/211#issuecomment-43677577 .

[JoannaUbels]

I'm still unwell, Alice knows where all my compounds are though and I should have an ok amount of 4 out of 5 of them

[mattodd]

All good - will be around shortly and we can talk, Alice.

On 21 May 2014 07:47, Joanna Ubels notifications@github.com wrote:

I'm still unwell, Alice knows where all my compounds are though and I should have an ok amount of 4 out of 5 of them

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/211#issuecomment-43687712 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

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[alintheopen]

No worries jo, I've got them. Feel better.

On Wednesday, May 21, 2014, Joanna Ubels notifications@github.com wrote:

I'm still unwell, Alice knows where all my compounds are though and I should have an ok amount of 4 out of 5 of them

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/211#issuecomment-43687712 .

[mattodd]

OK, this is the current list - the MMV compounds are available. The Sydney ones are mostly available - Alice to confirm. Selected from http://malaria.ourexperiment.org/biological_data/10048 We could remove 1-2 Sydney ones if there is too much duplication. Diverse structures, though it'd be nice to have more variation in solubility.

[alintheopen]

OSM-S-190, 191, 202 and 207 are available. There is probably just enough of OSM-S-187 (1-2 mg) and I can't locate OSM-S-188 right now but Jo says she has this in a flask somewhere.

[mattodd]

If have both, great. 188 is a good one to try and I'd like to send it. 187 non-crucial, but I also think that perhaps there is a bit too much duplication in using both 190 and 191. Great we have the others. Will now ping @PaulWillisMMV for final bit of advice here, and to check that my information on the current levels of compounds held by MMV is accurate.

[PaulWillisMMV]

Hi,

Thanks for compiling the list. I suspect we will not get all these tested in this run. I would drop MMV's 669784 and MMV668957 - they are v weakly potent and have high Log P so unlikely to be compounds or strategies we wish to follow-up on with further analogues so hERG data less critical. We have MMV's 669848 and 670936 in stock, there is no 671651 left.

I agree with Mat OSM-187 to 191 are rather similar and all high Log P - I would just choose one of these, until we have potency data, we can always send more later. We will probably need to send your samples to SPECS first to arrange testing, we will be in touch with details tomorrow. Can you prepare a list (with SMILES, MWt) of the compounds we will test

[mattodd]

OK, so the final set will be MMV669848, MMV670936, OSM-S-202, OSM-S-207 and of the similar set I'd really like to try an amine and its thioether analog, so I would like to go with OSM-S-188 (assuming we find/have it) and OSM-S-191. Spreadsheet coming in a moment.

On 22 May 2014 00:27, PaulWillisMMV notifications@github.com wrote:

Hi,

Thanks for compiling the list. I suspect we will not get all these tested in this run. I would drop MMV's 669784 and MMV668957 - they are v weakly potent and have high Log P so unlikely to be compounds or strategies we wish to follow-up on with further analogues so hERG data less critical. We have MMV's 669848 and 670936 in stock, there is no 671651 left.

I agree with Mat OSM-187 to 191 are rather similar and all high Log P - I would just choose one of these, until we have potency data, we can always send more later. We will probably need to send your samples to SPECS first to arrange testing, we will be in touch with details tomorrow. Can you prepare a list (with SMILES, MWt) of the compounds we will test

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/211#issuecomment-43761078 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

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[mattodd]

Final set http://malaria.ourexperiment.org/biological_data/10078/Screening_of_hERG_Activity_in_Series_4_Compounds.html so closing this issue.