Next batch of compounds sent for biological testing Feb 2018 #26
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Results are in. Data shown is the average of two runs. Data has been added to the Master List, and to the 'Biological Data currently not incorporated into the main Wiki sections wiki'
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OSM-S-525 potency is certainly encouraging but a re-syn and a replicated re-test at two assay centres would be in order (and can go in the paper as a diligent reproducability test). If this goes well we might even convince Tocris to put it up as a purchasable reference cpd |
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Hi @david1597 @edwintse does one of you have the above data (in whatever form we get them from ScienceCloud) posted somewhere on the ELN? We ought to have the primary data there, with the summary data here and on the wiki. Also, the image on the "Not yet added to the wiki" page also needs some link back to an ELN. We will need links of this kind to primary data for the paper. Also going to ping Neil Norcross for any comment on these data. |
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Primary data from ScienceCloud is now on my ELN. This ELN link has also been added to the Not Yet On The Wiki page. Also, pdf of the two runs are below as direct links: |
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Neil Norcross wrote by email today, after seeing the latest data. He recommended a focus on OSM-S-525: "I would resynthesize and retest this compound in the first instance, to ensure this is a true result. If it is, you might want to consider the 4 compounds below, to follow up on MMV1579341.
Reducing the number of aromatic rings and logP would be a priority. Do you have any mammalian (counter screen) cell data? Mouse hepatocyte, solubility and PAMPA data would also be very useful, if possible. (MHT - tox was included in the original screen? We're getting rat hep, sol soon) Key questions: How important is the NH of the indole? Is moving the NH2 from the para (MMV1579342) to the meta position better tolerated, in line with the indole NH? Does the 5 membered ring (mr) of the indole need to be aromatic or can the double bond be reduced (to the aliphatic 5 mr)? Can the logP be reduced further by introducing polar groups into the 5 membered ring (amide or sulphonamide) and are they tolerated? Also, how metabolically stable is the phenol ether (O-dealkylation)?" (MHT - this was assessed some time ago OpenSourceMalaria/OSM_To_Do_List#334) Strings: 2 3 4 |
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Regarding the sulfur compound this seems to be the only precursor that can be bought: (I think its worth saving up money to get norcross compound 4 made by a custom synth house like epichem) I believe compound 1 has already been made @maratsydney ?? I also wonder if a close relative of the norcross sulfonamide can easily be made (provided it's stable):
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Convergent thinking with Norcross on resyn/retest (but I was a week ahead :)
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While we are pushing for final data for the paper it would be good maybe for @david1597 & @mattodd to have a technical discussion with Dundee and MMV about a re-assay campaign for the front runners/ sub 100 nM hits and pivotal activity cliffs. Its great to see the raw data from Dundee (and full credit for their turnaround) but its clear from the charts that these are scoping IC50s with big error ranges (even missing the crucial points on the inflections in some cases). As @david1597 indicated elsewhere repeats are coming in with ranges of ~2-fold on a good day. Consequently, we are ending up with jellyfish SAR (i.e. wobbling values difficult to nail down). For comparison, data from @MedChemProf PfATP4_mutantsummary_MCPHS.pdf are more towards the tighter side we should aim for (e.g. +/- ~ 20- 30% ) although much depends on the extent of technical replicates and the data processing package used (e.g. EnzFitter or whatever) |
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What do you mean by jellyfish SAR - we have a bunch of diffrent stuff that works but dont know why? @cdsouthan |
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Further thoughts just in from Neil Norcross by email: A few more points to consider, if the ‘meta aniline’ is tolerated, you could replace the Cl for a F at the para position, which could work in a number of different ways: reduce logP, form an intra molecular H-bond to improve permeability, pull electron density away from the NH2, reducing nucleophilicity but also increasing H-bond potential of an NH (one H bond would be tied up with the F atom), this could reduce the reactivity of the aniline to possible glucoronidation also, so mouse hepatocyte data will be key here. In addition, you would need to get any aniline of interest tested for AMES, sooner rather than later. Also, changing the electronics of the ring can have a huge impact on whether a compound is AMES positive or negative. If the aniline at the meta position is key for activity and/or selectivity, you could always put a nitrogen atom at the para position (instead of the chlorine), giving you the amino pyridine, which could be very useful, if tolerated. The amino pyridine will modulate the pKa of the aniline (can increase pKa by 2 log units), so if aniline has a pKaH of ca. 5, the amino pyridine could have a pKaH of ca. 7. (The pKa of the amino pyridine can also be impacted by the electronics of the adjacent ring). If the aminopyridine is protonated at physiological pH, this may also improve your solubility and potentially, modulate in vivo properties such as volume of distribution and half-life. Also, compared to the aniline, the amino pyridine moiety can mitigate AMES and/or glucoronidation.
I would be cautious about adding the acid groups (meta or para), which is likely to kill your permeability (in vitro and in vivo) and may also impact on getting into red blood cells, for antimalarial screening. I appreciate that you can use acid bioiosteres as a replacement but it’s certainly something to be wary of. Strings 6 |
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Reading Neil's musings gave me rather crazy but possibly effective ideas: @mattodd @mcoster @drc007 What do you guys think? (I cannot seem to find S-triazine boronic acids anywhere so this might be a tricky one to make real) The boronic acid for this can be grabbed off of matrix - http://www.matrixscientific.com/boronic-acids/068426.html
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Is it possible to merge threads? |
The first batch of compounds for year (shown below) have now been shipped to Dundee for screening against P. falciparum.
UPDATE 24/3/18 RESULTS ARE IN AND ARE POSTED BELOW.
Dundee Compounds 260218.zip
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