edgriffen

overlays of candidates are viewable here:
THIQ_isomer_all_ennumerated_no_clash.cif.zip (107.4 KB)

pwkenny

Hi @edgriffen have you checked for potentially repulsive steric interactions between the substituent on the tetrahydroisquinoline N and the P1 isoquinoline in the bound conformation? What advantages do you see relative to the corresponding tetrahydroisoquinoline isomers? My recommendation would be to first check potency for structural prototypes (e.g. N-acetyl; N-methylsufonyl) before committing resource for synthesis of analogs with greater synthetic complexity. My comments also apply to the EDJ-MED-036ae2e9 and EDJ-MED-487c5e9f submissions.

edgriffen

Agreed - the structural prototypes are the first to make - hence splitting the design into 3 batches. The approach I used was a restrained conformational search and then just overlay the different conformations in place on the crystal structure ligand and filter out any clashes. I eyeballed the structures - I have some concerns about the sulfonyl urea conformations generally - I need to go back and look at the crystal structures we have for sulfonamides and sulfonyl ureas and see how they compare. The potency however appears to currently be poorly explained by interactions of groups on the tertrahydroisoquinoline, may be more due to conformational constraints, and changing the desolvation of the ligands.
In terms of advantage the 1-carboxylic acid accesses a different vector may access the P1’ side better.

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pwkenny

You’ll need to go ‘around’ the chiral center in order to get to P1’. Substitution at the chiral carbon would provide more direct access to P1’ while also locking the configuration.

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edgriffen

Agreed - only problem is getting substituents at the chiral centre is synthetically hard, and in some of the P2 ring systems the OR substituents eliminate rapidly to give the conjugated system.

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pwkenny

It might be worth looking at acetylene as a configurational lock. Geometrically it’s like a long freely rotatable single bond which makes it an interesting linker.