Submission EDJ-MED-e4b030d8

Topic automatically created for discussing the designs at:

Hi Ed @edgriffen

In case it’s useful, here is a relevant crystal structure with the dihydrobenzopyran ring system that I found in the CSD (pickings were not rich). The axial/equatorial differences do not appear to be particularly distinct although the substituent appears to be more axial than equatorial. I would anticipate that substitution of the carbon to which the carbonyl is linked will perturb the torsional preferences of the carbon-carbonyl bond and I can look into this in more detail if you would like. The chiral center in VLA-UCB-1dbca3b4-15 does look like an accident waiting to happen.

Thanks Pete, we have 4 crystal structures in fragalysis X11233, X11159, X10942,X10898. In particular X-11233, BRU-THA-a358fbdd-2, shows how the quaternary centre locks the amide axial. That analogue with the wrong P1 group and lack of a chlorine is completely inactive though. If you compare the structure to x10979, the carbonyls are almost perfectly overlaid. What it will do to the torsion barrier though is an interesting question.

Hi Ed,

My point was that locking may be unnecessary even though the protection of the chiral center would be be beneficial. The assay results will to tell you if the torsional profile is adversely affected by the substitution. One key question that needs to be addressed (as I’m sure you are trying to do) is what potency advantage does the dihydrobenzopyran confer relative to parent benzyl? There is also the question of whether a potency advantage is maintained when you attach substituents like the beta lactam in TRY-UNI-2eddb1ff-7.

An alternative annulation that I think would be worth pursuing could provide better contact (face rather than edge) with the protein surface although my primary interest in this scaffold is to provide access to the catalytic cysteine. The 5-membered analog has been ordered although I currently believe that access to the catalytic cysteine will not be as good.