PostEra

Submission JOH-SUS-a69c159d

COVID COVID_submissions
#1

Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/JOH-SUS-a69c159d

#2

I agree that it would be useful to get a handle on aldehyde oxidase activity since the the doubly-connected heteroaromatic nitrogen is a key pharmacophoric element which sits the periphery of the molecular structure. I would recommend using ADA-UCB-6c2cb422-1 (3-chlorobenzyl) as the structural reference for SAR analysis since information can be obtained without the need to resolve enantiomers.

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#3

Great point. Happy to chuck some of Baran’s reagent on that, wait 5 min and check for a +50 in the M.S. or hopefully a lack of a +50 in the M.S.! Moreover, the CHF2 product then blocks AO and could be tested!

#4

Thanks, @JSPEN. Really good points, we got back some initial metabolism data Friday and get the rest back early this week. Once we get that all together, hopefully can get some sense of what most needs fixing. We may indeed want to send some compounds your way.

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#5

we’re all prepared. Buying more reagent for assays. 2-subsituent in pyridine systems can also block other metabolism e.g. Cyp binding as well!

#6

Hi John, there is a lot of isoquinoline-based SAR (e.g. napthyridines and the phthalazine EDJ-MED-50fe53e8-1) for the 3-chlorophenylacetyl amides. My understanding is that pretty much anything that one does to the isoquinoline results in a loss of potency. I don’t know how bad the metabolism will be (the aromatic rings look particularly vulnerable) but I’m guessing that anything that we can learn about clearance mechanisms will be helpful. The mutagenic potential of hydrolysis products such as 4-aminoisoquinoline could also be a concern.

#7

Maybe a tiny F incorporation, even deuterium, might make a slight metabolism difference? C(D)=N. vs C(H)=N? There are OCH3 to OCD3 bioisosteric replacements in the lit with drugs on the market:

#8

Hi John, my understanding is that there are no advantages to deuteriation of aromatic carbons because C-H bond cleavage by CYPs is not rate-determining in these situations.

#9

good point, yes !

thanks