Submission PET-UNK-4dc48bbe

Topic automatically created for discussing the designs at:

The rationale for this submission is that the ‘imidic’ designs can be used to merge the 3-aminopyridine and quinolone series. I’ve discussed this with @mc-robinson previously and I’ll also mention @edgriffen who has has done design in the quinolone series. I’ve used the crystal structure for TRY-UNI-2eddb1ff-7 (x10789) for modelling and the crystallographic ligand has been included in the pdb file associated with the submission. I’ve also included the crystallographic ligands from the aligned x10959 (structurally prototypical isoquinoline ADA-UCB-6c2cb422-1) and x11294 (the quinolone EDJ-MED-6af13d92-3) crystal structures. The proposed binding modes for designs were generated using molecular mechanics energy minimization and potential binding modes have also been generated for previously submitted designs such as PET-UNK-abc197b8-1 | VLA-UCB-1dbca3b4-13 | PET-UNK-e8933450-1.

I would recommend starting with (previously submitted) PET-UNK-abc197b8-1 and PET-UNK-4dc48bbe-1 from the current design. The heteroaromatic rings in these designs are each flanked by two carbonyl groups which will tend to force them out of coplanarity with the acylurea substructure. This means that the advantage of isoquinoline over pyridine may be smaller in this substructural context than for the 3-aminopyridine-like series.

The chiral center in each of these dihydrouracils is a concern because locking it may result in loss of potency. While a spiro ring fusion (e.g. VLA-UCB-34f3ed0c-12) could be used to lock the configuration, this is likely to cut off access to the S4 subsite and the rigidification of the structure may well lead to loss of potency. VLA-UCB-1dbca3b4-13 and PET-UNK-e8933450-1 lack chiral centers and would synthesizing although I’d expect each to be less potent than the corresponding dihydrouracil PET-UNK-abc197b8-1. If the isoquinoline to pyridine exchange is well tolerated for for the dihydrouracils then the design team might consider prioritizing the pyridines PET-UNK-4dc48bbe-2 and PET-UNK-4dc48bbe-3 over the corresponding isoquinolines. I see the uracils PET-UNK-4dc48bbe-4 and PET-UNK-4dc48bbe-5 as less attractive than their regisomers because NH synthetic handle is ‘lost’ and I would not recommend synthesizing them in the first instance (I’ve included them just in case they are of interest to the design team).

The binding modes for the hydantoins are much less convincing than their dihydrouracil homologs and I see this as a result of the 5-membered rings being less able to pucker. VLA-UCB-29506327-1 exhibits only comparable potency to PET-UNK-c9c1e0d8-4 and I would recommend prioritization of the dihydrouracils over the hydantoins. Nevertheless, the design team may wish to explore the the consequences of having a spiro-fused dihydrobenzopyran and I’ve included PET-UNK-4dc48bbe-6 and PET-UNK-4dc48bbe-7 although I would advise against synthesizing these. If the design team wishes to pursue hydantoins then they may also wish to consider the 4-chorobenzyl analogs PET-UNK-4dc48bbe-8 and PET-UNK-4dc48bbe-9.

Pete could you register either the isoquinoline or 4 Me pyridine analogue of PET-UNK-abc197b8-1 - the SAR is very clear that lack of the Me / isoquinoline will impact potency and we have much better comparators for MMPA. Cheers, Ed

Hi Ed, the isoquinoline had already been submitted and I’ve just submitted the 4-Me analog as PET-UNK-eda34f30-1.