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Hi @edgriffen @mc-robinson

Discussion link hasn’t been set up yet for EDJ-MED-0d144977 so I’m commenting this way.

I would consider imidazole to be a CYP inhibition risk, especially at the periphery of the inhibitor structure. Another issue is that imidazoles tend to be partially protonated under physiological conditions which creates additional possibilities for off-target activity (including efflux). While you need a pendant hydrogen bond donor (or equivalent) for the tetrahydroisoquinoline scaffold to stabilize the bound conformation, I don’t believe this would still be the case for the dihydroisoquinolone scaffold (which lacks the pyramidal neutral nitrogen). Whether or not the hydrogen bond donor does indeed cause efflux, being able to dispense with it increases the range options and gives the design team more room to manoeuvre.

I would strongly recommend synthesizing the ester PET-UNK-c7ac4d9e-1 and/or its spirocyclic analog (which I’ve not actually submitted) since either of these will tell you whether you actually need a pendant hydrogen bond donor. These esters might also tell you whether a pendant amide is a permeability liability and, if the esters are equipotent with the corresponding amides, I’d be looking at 1,3,4-oxadiazole as an ester replacement. Here’s a PROTAC article which reports improvements in permeability resulting from amide to ester replacement. I should stress that I see replacing the pendant amide with an ester as a means for generating information that you can use in design rather than a solution to ADME problems.