Submission Details
Molecule(s):
O=C(Cc1cccc(Cl)c1)Nc1cncc2cnoc12
O=C(Cc1cccc(Cl)c1)Nc1cncc2cnsc12
O=C(Cc1cccc(Cl)c1)Nc1cncc2oncc12
O=C(Cc1cccc(Cl)c1)Nc1cncc2sncc12
O=C(Nc1cncc2cnoc12)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1cncc2cnsc12)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1cncc2oncc12)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1cncc2sncc12)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1cncc2cnoc12)[C@@H]1CCNc2ccc(Cl)cc21
O=C(Nc1cncc2cnsc12)[C@@H]1CCNc2ccc(Cl)cc21
O=C(Nc1cncc2oncc12)[C@@H]1CCNc2ccc(Cl)cc21
O=C(Nc1cncc2sncc12)[C@@H]1CCNc2ccc(Cl)cc21
O=C(Nc1cncc2cnoc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cnsc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2oncc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2sncc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cnoc12)[C@@H]1CS(=O)(=O)Cc2ccc(Cl)cc21
O=C(Nc1cncc2cnsc12)[C@@H]1CS(=O)(=O)Cc2ccc(Cl)cc21
O=C(Nc1cncc2oncc12)[C@@H]1CS(=O)(=O)Cc2ccc(Cl)cc21
O=C(Nc1cncc2sncc12)[C@@H]1CS(=O)(=O)Cc2ccc(Cl)cc21
O=C(Nc1cncc2cnoc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cnsc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2oncc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2sncc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnoc23)C1
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnsc23)C1
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3oncc23)C1
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3sncc23)C1
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnoc23)C1
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnsc23)C1
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3oncc23)C1
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3sncc23)C1
CC(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnoc23)C1
CC(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnsc23)C1
CC(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3oncc23)C1
CC(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3sncc23)C1
Design Rationale:
The designs in this submission aim to address metabolism of the isoquinoline P1 substituent (see also PET-UNK-e274cad4 submission notes). The designs use 4 heterocycles as P1 substituents in which the triply connected nitrogen of the P1 substituent in each of RUB-POS-1325a9ea-12 and RUB-POS-1325a9ea-13 is replaced with either oxygen or sulfur. One of the heterocycles is also an analog of the P1 substituent of JIN-POS-6dc588a4-22 and another is an isostere of EDJ-MED-076d6e64-1. I would anticipate that the 5-membered ring of each of the four heterocycles to be less electron-rich (potentially beneficial for metabolism) than the P1 heterocycle of either RUB-POS-1325a9ea-12 or RUB-POS-1325a9ea-13 ad this should be expected to reduce the hydrogen bond basicity of the nitrogen in the 6-membered ring that accepts a hydrogen bond from the protein. The 4 P1 substituents can be assessed for potency by synthesizing the first 4 designs (3-chlorobenzyl at P2) although I have linked them to a number of other scaffolds (e.g. chromane) in the same sequence to provide the design team with additional options in case these are helpful.
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 PDB file associated with this submission contains the following: [1] X11612 A chain [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-38] Designs 1-36.