Submission Details

Design Rationale:

The presence of a secondary amide is a potential ADME risk factor (hydrolytic instability; active efflux; excessive polarity). This submission is related to PET-UNK-3324058f. The four designs in this submission combine replacement (with cyano which is metabolically rugged, more hydrolytically stable than amide and can make contact with the P1 isoquinoline in an analogous manner to pendant amide) of the pendant secondary amide substituent on the P2 dihydroisoquinolone nitrogen with four C7 substituents on the P1 isoquinoline that are being used by the design team to reduce metabolism. Although the pendant secondary amide on a P2-tetrahydroisoquinoline scaffold does not appear to make contact with the protein, it is not easily replaced because it adopts an ‘unusual’ conformation (the amide NH eclipses the tetrahydroisoquinoline nitrogen lone pair). However, this ‘unusual’ conformation becomes the ‘default’ conformation on the dihydroisoquinolone scaffold which suggests that the pendant secondary amide can be more easily replaced on this scaffold. I’ll link some more detailed discussion in a comment to this submission. Each design has also been submitted as a racemate.

Other Notes:

Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3-6] Binding modes predicted for Designs 1-4.

Inspired By:

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