Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/FRA-DIA-e29753f2
@edgriffen @alphalee, this one is an even more super-logical follow-up from yesterday’s discussion. Turns out Jag got there first, back in June, JAG-UCB-c61058a9-45, though it was never made.
Great prompt Frank - thanks.
Hi @frankvondelft @edgriffen @alphalee I think that it is a good idea to examine the effect of replacing the isoquinoline with a quinolone. However I would argue that would be better to perform the replacement on the the chlorobenzyl analog ADA-UCB-6c2cb422-1 which would allow direct comparison with the other P1 groups. The dihydrobenzopyran P2 group is not ideal as an SAR reference because it is necessary to resolve the enantiomers in order to make the reference.
You may wish to consider the cost (three additional non-hydrogens; increased electron-richness of benzene ring; racemizable chiral center that will require at least an additional non-hydrogen to ‘lock’) at which the modest increase in potency has been achieved in going from ADA-UCB-6c2cb422-1 to VLA-UCB-1dbca3b4-15. It is possible that the relevant compound has already been proposed although I have no means of checking this.
Hi Pete, you can substructure search submissions here: https://postera.ai/covid/submissions/search - the work you suggest is currently being expanded with a range of bicyclic heteroaromatics with a hydrogen bond acceptor present.
I just noticed (now I realised that to get substructures, you have to select Substructure in the search) that a quinolone with flipped amide was already made, back in August: MAT-POS-3b92565d-6. Only 80uM in fluorescence, and no RapidFire or crystal structure. @Daren_Fearon, @LizbeK, any idea what happened with that compound? (From CDD, I infer it’s shipment 21.)
Got one dataset last week but don’t see it bound. Will repeat when we have some more xtals.
Thanks for the info, Ed, and it may be worth keeping an eye on pKa (I don’t know the relevant physiological pH for this target). Here are pka values (in parentheses) for 4-azaindole ( 6.9), 5-azaindole (8.3 ) 6-azaindole (7.9). Generally one can pump more hydrogen bond acceptor potential into an a aromatic [nX2] nitrogen in a 5-membered ring before it starts protonating than in a 6-membered ring. CYP inhibition is always a risk with aromatic [nX2] nitrogen (possibly more so when in a 5-membered ring than in 6-membered ring). It may be an idea to get some CYP inhibition measured in case this highlights problems with particular heterocycles.
Looks like you already have some SAR for the effects of aza-substitution of ADA-UCB-6c2cb422-1 (see MAT-POS-f7918075-5 | MAT-POS-bb423b95-2 | MAT-POS-bb423b95-1). Naphthyridine nitrogens would be expected to be weaker HB acceptors than isoquinoline nitrogen and we presented pKBHX predictions for naphthyridines that support this view.
I’d expect the the [nX2] HB acceptor of PET-UNK-8df914d1-2 to be stronger than the isoquinoline nitrogen of the reference compound. I think that the hydrogen bond geometry is probably better for the isoquinoline although there may be conformational factors as well. I’m guessing that a second [nX2] nitrogen (lone pair repulsion) in the 5-membered ring might improve the HB geometry situation even though this tactic (EDJ-MED-50fe53e8-1) resulted in loss of potency when applied to the isoquinoline. The energy cost of achieving the bound conformation may also vary with heterocycle.
@frankvondelft - we don’t bother investigating IC50 differences that is so far outside the potency range (that is inactive when applying our original cut-off filter of 50% inhibition at 50 uM) and with less than 2-fold difference.