Submission Details
Molecule(s):
Cn1ncc2cncc(NC(=O)[C@@H]3CCS(=O)(=O)c4ccc(Cl)cc43)c21
COc1cc2c(NC(=O)[C@@H]3CCS(=O)(=O)c4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@@H]3CCS(=O)(=O)c4ccc(Cl)cc43)c2cn1
Cn1ccc2cncc(NC(=O)[C@@H]3CCS(=O)(=O)c4ccc(Cl)cc43)c21
O=C(Nc1cncc2cc(F)ccc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccc(F)cc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cc(F)c(F)cc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccncc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cnccc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
The submission consists of 9 designs based on a 6-membered cyclic sulfone scaffold that are intended to address the issue of isoquinoline metabolism. I currently consider the 1-methylpyrazolopyridine to be the isoquinoline replacement (Design 1; see submission notes for PET-UNK-e274cad4) with the most potential to reduce metabolism with minimal loss of affinity and I’ve also included two methoxynaphthyridines (Designs 2 and 3; see submission notes for PET-UNK-f4e47ebd). The 7-fluoro, 6-fluoro and 6,7-difluoro isoquinolines have been included as Designs 5-7 (I consider Design 5 to be of a higher priority than Designs 6 or 7).
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 from complex with Design 3 [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-11] Designs 1-9.