Currently the design team are looking for P1 substituents with improved metabolic relative to isoquinoline. The aromatic amines from which the P1 substituents are derived would raise generic concerns (amino group attached to aromatic carbon) about genotoxicity. Pharma companies typically have in house genotoxicity data (e.g. Ames assay results) as well as models trained using their proprietary data. While I don’t think that Pharma companies will make all their data publicly available, I’m guessing that they would be prepared to check databases and run models for specific aromatic amines. My understanding is that there are a number of people working in Pharma who are associated with the COVID Moonshot and I would recommend that you explore possibilities with them.
The majority of the inhibitors of interest in the 3-aminopyridine series are chiral and this is a potential safety/development issue if the configuration is not locked (e.g. with methoxy) since the chiral center is next to the amide carbonyl. As discussed previously, it is possible that locking the configuration of the chiral center could alter the existing SAR. This is most likely to be an issue for tetrahydroisoquinolines at P2 with relatively large substituents on nitrogen such as MAT-POS-dc2604c4-1 | EDJ-MED-1981ceba-4 | MAT-POS-4223bc15-23. I would recommend that you assess the various configurational locks of interest sooner rather than later if you think that it’ll be necessary to lock the configuration of the chiral center.