Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/VLA-UCB-50c39ae8
Acetylation of the amide nitrogen in the 3-aminopyridine series looks like an interesting idea. This structural modification is likely to weaken the hydrogen bond basicity of the amide carbonyl oxygen that accepts a hydrogen bond from from the backbone amide NH of E166. From my initial assessment using the Cambridge Structural Database (CSD), it looks like the acetyl group of VLA-UCB-50c39ae8-1 will be in the wrong conformation for accepting a hydrogen bond from the backbone NH of G143 (I can share the analysis if this is of interest). This provides support for cyclic analogs such as VLA-UCB-50c39ae8-3.
In general, I would recommend developing these ideas from ADA-UCB-6c2cb422-1 as a starting point rather than VLA-UCB-1dbca3b4-15 given that the modest additional potency of the second compound has been achieved at the cost of additional complexity (chiral center; fused ring) and risk (racemization). The additional rigidity of the spiro structures reduces margins of error for accommodating the chloroaryl substituent in the S2 subsite (this is a molecular complexity argument). As such, I believe that it would be better to synthesize the spiro analogs only after the annulations of the amide have been shown to be beneficial.
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