Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3cnn(C)c23)CCS(=O)(=O)c2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CCS(=O)(=O)c4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@]3(OC)CCS(=O)(=O)c4ccc(Cl)cc43)c2cn1
CO[C@@]1(C(=O)Nc2cncc3ccn(C)c23)CCS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CCS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(F)cc23)CCS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(F)cc23)CCS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccncc23)CCS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnccc23)CCS(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
The submission consists of 9 designs based on a cyclic sulfone scaffold that are intended to address the issue of isoquinoline metabolism. The designs in this submission are related to those in the PET-UNK-2c6614b6 submission in that each is a methoxy analog of a design in the previous submission (the methoxy substitution locks the confugration of the chiral center and appears to be beneficial for achieving antiviral activity). 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 (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 from energy-mimimized complex with PET-UNK-1b92fa34-5 [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-11] Designs 1-9