Does RA-3301 Really Contain a PAINs Motif?

[mattodd]

The "Mannich Phenol" motif that is potentially problematic in the 3301 series is mentioned in

https://pubs.acs.org/doi/10.1021/acschembio.7b00903

and

https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra06736d

Neither is an exact match. The flexibility of the motifs shown implies there is the possibility of a need for chelation if the motif is to be a problem. We don't have that, do we?

The second paper above does say that the PAIN effect disappears when the OH is methylated, and I see that that is a current synthetic target, which makes a lot of sense.

The papers don't provide a reason why the motif is an issue, but just show that they show up slightly more freqently than they ought, based on chance.