Submission Details
Molecule(s):
Cn1ncc2cncc(NC(=O)[C@@H]3CS(=O)(=O)c4ccc(Cl)cc43)c21
COc1cc2c(NC(=O)[C@@H]3CS(=O)(=O)c4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@@H]3CS(=O)(=O)c4ccc(Cl)cc43)c2cn1
Cn1ccc2cncc(NC(=O)[C@@H]3CS(=O)(=O)c4ccc(Cl)cc43)c21
O=C(Nc1cncc2cc(F)ccc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cc(F)c(F)cc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccc(F)cc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccncc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cnccc12)[C@@H]1CS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnn(C)c23)CS(=O)(=O)c2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CS(=O)(=O)c4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@]3(OC)CS(=O)(=O)c4ccc(Cl)cc43)c2cn1
CO[C@@]1(C(=O)Nc2cncc3ccn(C)c23)CS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(F)cc23)CS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(F)cc23)CS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccncc23)CS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnccc23)CS(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
The submission consists of 18 designs based on a five-membered cyclic sulfone scaffold that are intended to address the issue of isoquinoline metabolism (the rationale for assessing five-membered cyclic sulfones is given in the submission notes for PET-UNK-022eab87). This submission parallels the PET-UNK-2c6614b6 and PET-UNK-4b4f2bb7 submissions (six-membered cyclic sulfone). Each of the second nine designs is the methoxy analog of one of the first nine designs (methoxy locks configuration of chiral center and may be advantageous for translation of enzyme inhibition to activity in the cell-based assays). I currently consider the 1-methylpyrazolopyridine to be the isoquinoline replacement (Designs 1/10; see submission notes for PET-UNK-e274cad4) with the most potential to reduce metabolism with minimal loss of affinity and I’ve also included methoxynaphthyridines (Designs 2/11 and 3/12; see submission notes for PET-UNK-f4e47ebd). The 7-fluoro, 6,7-difluoro and 6-fluoro isoquinolines have been included as Designs 5/14, 6/15 and 7/16 (I consider Designs 5/14 to be of a higher priority than Designs 6/15 or 7/16).
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) [3-20] Designs 1-18.