Submission Details
Molecule(s):
PET-UNK-e274cad4-1
Duplicate of:
RUB-POS-1325a9ea-14
Cn1ncc2cncc(NC(=O)Cc3cccc(Cl)c3)c21
Cn1ncc2cncc(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)c21
Cn1ncc2cncc(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)c21
Cn1ncc2cncc(NC(=O)[C@@H]3CCNc4ccc(Cl)cc43)c21
Cn1ncc2cncc(NC(=O)[C@@H]3CS(=O)(=O)Cc4ccc(Cl)cc43)c21
Cn1ccc2cncc(NC(=O)Cc3cccc(Cl)c3)c21
Cn1ccc2cncc(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)c21
Cn1ccc2cncc(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)c21
Cn1ccc2cncc(NC(=O)[C@@H]3CCNc4ccc(Cl)cc43)c21
Cn1ccc2cncc(NC(=O)[C@@H]3CS(=O)(=O)Cc4ccc(Cl)cc43)c21
Design Rationale:
This submission is derived from JIN-POS-6dc588a4-14 (synthesis currently in progress) in which the P1 substituent is a 5-azaindole linked at C7. I would anticipate that an intramolecular hydrogen bond between the azaindole NH of JIN-POS-6dc588a4-14 and the amide carbonyl oxygen may impose an energetic penalty for adopting the bound conformation. A pKa of 8.3 has been reported ( https://doi.org/10.1039/JR9600001794) for 5-azaindole and it is possible that JIN-POS-6dc588a4-14 will be predominantly protonated under physiological conditions (I would anticipate that the amido substitution at C7 will be base-weakening). The 1-methyl substituent would be expected to reduce the energetic penalty incurred by adopting the bound conformation. The designs in this submission consist of five 1-methyl pyrazolopyridines (the additional aza-substituent will ensure neutrality of the P1 substituent under physiological conditions) and the five corresponding 1-methyl-5-azaindoles. 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 6 (no need to resolve enantiomers in order to generate SAR) although I would also recommend synthesizing Design 2 and Design 7 (P2 chromane) since there does a appear to be some (potentially beneficial) contact between the 1-methyl substituent and C3 of the chromane ring. I have included designs with other P2 subsituents in case these are also of interest to the design team
Other Notes:
Protein-ligand complexes (X11612 A chain) were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The X11612 A chain was used for modelling. The PDB file associated with this submission contains the following: [1] X11612 A chain [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-5] Binding modes predicted for MIC-UNK-50cce87d-3 | BEN-DND-a7517465-1 | EDJ-MED-d1555997-2 (S enantiomer) [6-15] Binding modes predicted for designs 1-10.