Submission PET-UNK-c7ac4d9e

Topic automatically created for discussing the designs at:

Hi @edgriffen @RGlen @mc-robinson

The single design (an ester) in this submisssion, replaces the amide NH of EDJ-MED-015fb6b4-2 with oxygen, with a view to addressing the potential permeability of the amide. This ester should be as synthetically accessible as the corresponding amide EDJ-MED-015fb6b4-2 and it would enable us to assess the importance of the pendant amide NH for potency. I see the ester primarily as a means with which to map SAR (potential for hydrolysis) and would be looking at ester mimics such as PET-UNK-37251634-3 if potency is comparable with EDJ-MED-015fb6b4-2.

A conformational feature common to the tetrahydroisoquinolines MAT-POS-4223bc15-23 and MAT-POS-e194df51-1 is a bond (methylene-carbonyl in former and sulfur-carbon in latter) that is orthogonal to the ring plane. This would generally be unfavorable because the bond is gauche with respect to each of the N-C bonds of the tetrahydroisoquinoline (typically a bond like this would orient anti to one of the N-C bonds and gauche to the other). In the case of MAT-POS-e194df51-1 the orientation of the bond simply reflects the natural conformational preference of sulfonamides. MAT-POS-4223bc15-23 is more interesting in that the conformation reflects the tendency of the NH of the pendant amide to align with the tetrahydroisoquinoline nitrogen line pair. As discussed with Bobby, interaction with the carbonyl oxygen of the central amide may also contribute but, even in its absence, the pendant amide NH will tend to align with the tetrahydroisoquinoline nitrogen.

What is the unnatural conformation for tetrahydroisoquinoline is the natural conformation for dihydroisoquinolone (I don’t actually think a pendant ester would work well on a tetrahydroisoquinoline). This means that some of the pendant group SAR may differ between the tetrahydroisoquinoline and the dihydroisoquinolone.