Submission EDJ-MED-7587a9ee

Topic automatically created for discussing the designs at:

Hi Ed,

The spiro analogs are pretty rigid and you’ll lose potency if everything’s not in the right place (it would be prudent to anticipate non-additive SAR). The chromane analog of Design 1 ( VLA-UNK-cf7facf1 IC50: 0.7 µM) is not especially potent and I would consider it unwise to assume that the potency of the spirocyclic inhibitor is necessarily predictive of non-spirocyclic analogs such as PET-UNK-4dc48bbe-6.

I have suggested that introduction of a second amide to mimic the quinolone amide oxygen will be advantageous for potency and believe that a 6-membered ring (e.g. dihydrouracil) will be better than a 5-membered ring (e.g. hydantoin). I would recommend that the dihydrouracil PET-UNK-abc197b8-1 (racemate: VLA-UCB-1dbca3b4-18) be synthesized ahead of spirocyclic analogs. In the light of the Jorgensen study, I think that it would also be worth looking at PET-UNK-e8933450-1 and VLA-UCB-1dbca3b4-13. Spirocyclic dihydrouracil analogs (e.g. VLA-UCB-34f3ed0c-12 | VLA-UNK-c65c1026-6 | VLA-UNK-c65c1026-4) have been submitted.