Submission Details

Design Rationale:

The designs in this submission replace the pendant secondary amide of EDJ-MED-015fb6b4-1 (IC50 of des-methoxy analog EDJ-MED-015fb6b4-2 is 56nM) with 8 heteroaromatic amide mimics that all lack a heteroatom-based hydrogen bond donor (configuration of chiral center in each design in PET-UNK-37251634 submission is locked with methoxy). The pendant amide does not appear to form hydrogen bonds with the protein although there does appear to be some non-hydrogen bonded contact between the amide and the P1 isoquinoline in the crystal structure (P1090) for the complex with MAT-POS-4223bc15-23. My view is that the potency benefits resulting from the NH of the pendant amide are due to stabilization of the bound conformation. The designs fall into two groups according to whether the heterocycle has two hydrogen bond acceptor atoms (Designs 1-5) or a single hydrogen bond acceptor atom (Designs 6-8). My view is that having two adjacent nitrogen atoms in an aromatic ring is likely to be beneficial if CYP inhibition or metabolism involving aromatic nitrogen are issues. I recommend focusing on Designs 1-5 in the first instance, using synthetic accessibility to set priority. I’m assuming that compounds will initially be synthesized as racemates so I have included these in the submission as Designs 9-16 (also useful for identifying duplicate submissions).

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] P0601 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3] Binding mode predicted for EDJ-MED-015fb6b4-1 [4-11] Binding modes predicted for Designs 1-8.

Inspired By:

EDJ-MED-015fb6b4-2

PET-UNK-37251634-4

PET-UNK-37251634-7

PET-UNK-37251634-3

MAT-POS-4223bc15-23

PET-UNK-37251634-8

PET-UNK-37251634-5

PET-UNK-37251634-2

PET-UNK-37251634-1

EDJ-MED-015fb6b4-1

PET-UNK-37251634-6