Submission Details

Design Rationale:

This submission is derived from RUB-POS-1325a9ea-14, the 1-methyl analog of RUB-POS-1325a9ea-12 (IC50 = 2 μM) and consists of methoxy analogs of eight of the designs in the PET-UNK-e274cad4 submission. I expect the 1-methyl group of RUB-POS-1325a9ea-14 to stabilize the bound conformation (relative to the des-methyl analog RUB-POS-1325a9ea-12). A pKa of 8.3 has been reported ( https://doi.org/10.1039/JR9600001794) for 5-azaindole although the pyrazolopyridine of RUB-POS-1325a9ea-14 should be predominantly neutral under physiological conditions. The designs in this submission consist of four 1-methyl pyrazolopyridines (the additional aza-substituent will ensure neutrality of the P1 substituent under physiological conditions) and the four corresponding 1-methyl-5-azaindoles (the amido substitution at C7 may be sufficiently base-weakening to render these neutral under physiological conditions). I would anticipate (electron withdrawal by aza substituent) that a pyrazolopyridine will be more resistant to metabolism of the heterocyclic ring than the corresponding azaindole. The ideas behind this submission can be tested with Design 1 and Design 5 although I‘ve included designs with other P2 subsituents in case these are also of interest to the design team.

Other Notes:

Protein-ligand complexes (P0157 A chain) were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The PDB file associated with this submission contains the following: [1] P0157 A chain [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3] Binding mode predicted for JOH-UNI-6e27fddc-1 [4-11] Binding modes predicted for designs 1-8.

Inspired By:

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