Submission Details

Design Rationale:

The submission consists of 5 designs based on the methoxychromane scaffold that are intended to address potential metabolism of the P1 isoquinoline (see also PET-UNK-b1ef24dc submission notes). The P1 heterocycles in the first 4 designs would all be expected (on the basis of reduced electron density in the non-pyridine ring) to have better metabolic stability than isoquinoline. However, the effects on potency from substitution of these for isoquinoline are unknown (my recommendation would be to first synthesize these as the corresponding 3-chlorophenylacetamides which are included as inspirations for the submission). Design 5 would be expected (based on the JIN-POS-6dc588a4-22/ADA-UCB-6c2cb422-1 matched molecular pair) to be equipotent with PET-UNK-29afea89-2 although the metabolic stability rationale is weaker.

Other Notes:

Design 5 is the S-enantiomer of MAR-UCB-fd2e172f-24 and this is indicated in the PDB file associated with the submission. 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) [3-7] Designs 1-5

Inspired By:

EDJ-MED-d2def222-2

JIN-POS-6dc588a4-22

RUB-POS-1325a9ea-13

PET-UNK-29afea89-2

RUB-POS-1325a9ea-12

EDJ-MED-d2def222-1

RIT-HTT-61afd604-1

PET-UNK-b1ef24dc-2

PET-UNK-b1ef24dc-1

PET-UNK-b1ef24dc-4

MAR-UCB-fd2e172f-24

RUB-POS-1325a9ea-14

PET-UNK-b1ef24dc-3