Meeting Discussion Point 3: Potency

[mattodd]

Background to Meeting on May 24th 2016 (#386).

Question: Based on what is known of the SAR for Series 4, and after factoring in considerations from #388 and #389, are there unexplored motifs that could be tried in order to improve potency? Question: Based on the sensitivity to substitution of the aromatic rings, is there simple matched pair analysis that could be executed on the series to predict better potency?

Resources:

OSM Series 4 summary wiki - good place to browse structures. Lab books: Labtrove, Labarchives (Ed Tse, Chase Smith). See the Biological Evaluation ELN in particular for this Issue. Compound Database: All OSM Compounds in Google Sheet, interactive view on Cheminfo - also good for browsing SAR, direct download of Series 4 SDF.

Comments/suggestions below are welcome, as well as (briefly please) during the webinar meeting and its follow-up (#394).

Relevant background:

The latest batch of compounds currently being biologically evaluated for potency is here (also in #384).

Previous biological evaluations: Nov 2015, June 2015, May 2015 Edinburgh, November 2014, July 2014

Recent discussions on synthetic planning are in #358. See also: June 2015 ELN post, March 2015 ELN Post, December 2014 Xmas Shortlist, and in issue #301.

Targets currently being synthesized are below. They include a homologous series of thioether, sulfoxide and sulfone and two cubane-containing compounds (#379).

[MFernflower]

@mattodd @drc007 Quick thing about the NE Cubane - Isn't iodine in drugs a really bad idea????

Would this work to exchange the iodine for chlorine????? http://pubs.acs.org/doi/abs/10.1021/ja028865v

Sorry about the repost of this comment to GitHub - I was having an issue with my browser

[edwintse]

Another possible set of targets. Having no luck previously in making the triazole linker compound, a ether-triazole linker was thought to be an alternative. Will attempt synthesis shortly.

[MFernflower]

Seems like an interesting thing to test!

[mattodd]

Neil Norcross from The University of Dundee emailed after attending the meeting. He contributed an SDF of suggestions for the northeast (RHS) which are shown graphically below (with numbers to aid discussion and with logP derived from DataWarrior). Neil wrote (posting with permission): "The SAR on the RHS looks very interesting as it stands and some of the suggestions attached could potentially reduce aromaticity and include a ‘protonatable centre’, whilst still retaining or improving in vitro activity. As a suggested logP cut-off, 3.6 might be an option for the benzyl morpholine suggestion (N16) (although arguably, this might want to be closer to 3 in the future). Something to bear in mind also is that logP and PSA are not always indicative of either solubility and/or permeability. Structure and flexibility can also play an integral part."

Thanks Neil for these interesting suggestions. In my mind I had discounted N-linked rings in the northeast, but there are examples here of reasonable potency. What do people think about these? Alice/Ed - are these synthetically straightforward given a consideration of commercial availability of materials?

Neil emailed as I was posting this: "The difluropiperidine on the RHS (N6) would be really interesting as a starting point. The positioning of functionality seems to be crucial for activity, as you can see from where the Cl atom is placed. The extra interactions from the fluorine atoms could help you win back some potency, whilst introducing the protonatable centre (amidine-like moiety, between the bicyclic core and the piperidine).

Regarding potency, if you do lose a bit from changes at the RHS but significantly improve physicochemical properties and reduce metabolic clearance/improve solubility, this could provide you with a better compound for in vivo experiments. A focus might then be to move back to the left hand side and optimise there.

One last question, does all your SAR track on the right hand side, with the two different linkers on the left hand side (O-alkyl vs. amide)?"

Answer: I don't know - we need to check that.

[MFernflower]

@mattodd I had a bit of a think about what Neil said and came up with this:

[MFernflower]

@mattodd The 4,4-DIFP fragment is stocked by SA!!!!

http://www.sigmaaldrich.com/catalog/product/aldrich/665525?lang=en&region=US

We could use Buchwald-Hartwig coupling to join it to the TP core

[MedChemProf]

The idea certainly has merit, but I think the hypothesis could be tested with making at most two compounds using the functionality he denotes as N3 and N6. As you pointed out, there are already analogs similar to these that show activity. Analogs attached to the triazole ring using a sp3 carbon (like N8) should probably be avoided for the present.

[mattodd]

Preparing files for meeting tomorrow (#394). Summary of recent extra proposed compounds for discussion.

[MFernflower]

@mattodd quick correction on your graphic - the sulfonamide idea was a joint effort bewtwen Ed and me

[MedChemProf]

@mattodd Below are the slide additions on current status: Scheme 1 below shows current progress toward our first scaffold hop target. We have synthesized the intermediate successfully and will be adding the left hand ethoxy linker in the next few days. We have had to switch to the para-fluoro analog since our order for additional 2-(3,4-Difluorophenyl)ethan-1-ol is on back order until the end of July. Scheme 2 shows the planned route to the second scaffold hop target. It is understood that the addition of the tetrazole will result in a mixture of the 1,2- and 1,3- products. The two will have to be separated either prior to or after the ethoxy linker is added. The synthesis of the reversed amides is proceeding again (Scheme 3). The azide was reduced on 6/6/16 and is undergoing purification. Although the previous amide coupling with the amine failed (HBTU/HOBT), we are confident that we can get the reaction to work using another coupling reagent such as COMU. We did take a few milligrams of the amine that was recovered in the HBTU coupling and acylated it successfully with acetic anhydride as a test reaction. We have also started the synthesis of the 4-methylsulfone analogs (Figure 1 below): Finally, there are some plans to incorporate the triazine (Figure 2 below) in some of the above reaction schemes, but any efforts are taking a back seat to the pyrazine at the moment.

[mattodd]

Neil Norcross from the University of Dundee emailed re the synthesis of his N6 suggestion, above: "Regarding the synthesis of 4-difluoropiperidine (and similar substituted piperidines) on the RHS of your lead scaffold; if you have access to a microwave, I would try nucleophilic displacement of the ArBr, 2 equivalents of your amine in a solvent such as NMP. 150 DEG C, 30 mins to start with. A higher temp for more or less time can then be tried later if needed. (e.g. 200 deg C for 10 mins ) I would certainly try this before moving to Buchwald conditions." Thanks Neil, that's very useful. Yes this is what we're hoping, that an addition-elimination will be possible at that position. I'm sure there's a microwave reactor around here somewhere. @edwintse do we have any suitable brominated material that we could play with, or should this be added to the hotlist of compounds needed in the short term?

[alintheopen]

@mattodd Here are my targets for the moment.

[edwintse]

@mattodd Current targets

Scheme 1 shows route to ether-triazole linker. Tried multiple methods of azide synthesis. Very difficult to tell whether azides were made as NMR shifts aren't very significant. Click reaction of azide with benzyl group was done today and seems to have gone. Will attempt to couple to TP core next.

Scheme 2 shows most recent method for sulfonamide synthesis. Previous methods have failed. Attempted today but product doesn't seem right. Will attempt again tomorrow.

Scheme 3 shows the planned route to make the cubane aldehyde then coupling to core.

The homologous thioether series is complete as are both NW cubanes. The Ketone and the Tianyi will be worked on by Haverford College students as well.

[mattodd]

Neil Norcross commented today: "Hi Mat, When I came up with some ideas for the NE RHS, I was not aware of some of your previous SAR, after recently getting involved with OSM. Now that I am better acquainted, my 'top picks' for things to try first would be the following: N6,7,9,10,15,16.

This selection will hopefully provide you with some useful ideas for your subsequent steps. Note, N16 has a predicted logD of 3."

[MFernflower]

@alintheopen I think Haverford might be making the acid test: #405

[MFernflower]

@mattodd I'm a bit interested in compound N1 - If it proves potent this could be a fantastic breakthrough as the right hand aldehyde is $50 for 100 grams (99% pure) from SA http://www.sigmaaldrich.com/catalog/product/aldrich/250376

[MFernflower]

@mattodd @edwintse @alintheopen Why not test a right hand bromoarene? http://bit.ly/29HLl9H

[MFernflower]

Hello all! I have came up with variations of the norcross idea. I'm on holiday at the moment so I was only able to sketch them up and zip up the mol files:

NORCROSS_MODS.zip

[mattodd]

Housekeeping insertion of link to Gunnlaugsson/Scanlan 2017 paper describing alternative condensation route to Norcross-like N-linked compounds (10.1021/acs.orglett.6b03645).

[MFernflower]

@mattodd Paywalled sadly