Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/PET-UNK-e8c7a26f
I’ll mention @londonir @JSPEN @mc-robinson @Daren_Fearon @AnthonyA who are interested in covalent inhibitors.
Before getting locked into using chromane substructure with the acrylamide warhead, I would recommend that the chlorobenzyl analog VLA-UCB-05e51b3f-16 be synthesized since the additional rigidity of the chromane may prove to be less advantageous when trying to achieve transition state geometry than when binding is reversible. The Michael acceptor in these compounds is likely to be more electrophilic than a normal acrylamide and I’d recommend that reactivity be assessed as soon as possible since de-tuning the reactivity is likely to be difficult (at least in a way that doesn’t compromise k.inact). In cheminformatic terms, this can be seen as pruning the decision tree. I think that it would also be worth synthesizing the propynoyl analog DAR-DIA-56cf811e since this is likely to be both more electrophilic and better able to adopt the transition state geometry.
The two designs in the submission are intended to help map SAR. Structural features that are optimal for reversible inhibitors may be less optimal for irreversible inhibitors and SAR does not always track between the two types of inhibitor. In the first design, the chloro of the P2 substituent of VLA-UCB-05e51b3f-16 is moved from C3 to C4. In the second design, the isoquinoline P1 substuent is pruned to pyridine and this is likely increase flexibility which may make the transition state geometry more accessible. The carbonyl groups that flank the P1 substituent would tend to attenuate the advantage of isoquinoline over pyridine even if the inhibition was reversible.
Thanks @pwkenny. We’re trying. Not obvious in terms of synthesis, stability, yield but we’re making a few inroads with some scaffolds and some warheads. Will submit on Postera once we’ve sent to Diamond. If they’re low yielding, poor yield and, most importantly, difficult to isolate and unstable the “aint gonna be drugs”…
We have the X-ray structure of MAT-POS-090737b9-1 and it should be online later today which might be of interest for these discussions.
Thanks, Daren, and looking forward to seeing it. I think the crystal structure would provide a useful starting point for generation of a transition state model and perhaps somebody working with the project has the capability to do this. Transition state geometry is one factor that I’d guess will limit the potency that we can achieve with this chemotype.
Agreed, John, and good luck with the synthesis! I would anticipate poor physicochemical characteristics structures partly these because the imidic carbonyl Os are weaker (more like ketone O) than amide carbonyl Os as HB acceptors.
Sorry - got ahead of myself, should appear on Fragalysis tomorrow.