Submission Details
Molecule(s):
Cn1ncc2cncc(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)c21
O=C1NC[C@@H](C(=O)Nc2cncc3cn[nH]c23)c2cc(Cl)ccc21
O=C1NC[C@@H](C(=O)Nc2cncc3sccc23)c2cc(Cl)ccc21
PET-UNK-7279c968-4
Duplicate of:
PET-UNK-b38839dc-12
O=C1NC[C@@H](C(=O)Nc2cncc3occc23)c2cc(Cl)ccc21
O=C1NC[C@@H](C(=O)Nc2cncc3cc(F)ccc23)c2cc(Cl)ccc21
COc1cc2c(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)cncc2cn1
CN(C)c1cc2c(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)cncc2cn1
PET-UNK-7279c968-8
Duplicate of:
PET-UNK-b38839dc-13
COc1cc2c(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)cncc2cc1F
CN(C)c1cc2c(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)cncc2cc1F
Design Rationale:
The designs in this submission combine the lactam P2 subsituent of MIC-UNK-91acba05-1 with 9 variations of the parent isoquinoline (IQ) that are intended to address potential metabolism at C7/C8 of isoquinoline while minimizing loss of potency. Designs 1/2 (pyrazolopyridine: aza substituent likely to protect against metabolism and potency loss relative to IQ is small). Design 3 (6-azabenzothiophene: equipotent to IQ and key question is whether sulfur is more resistant to metabolism than C7/C8 of IQ). Design 4 (6-azabenzofuran: oxygen will more resistant to metabolism than sulfur of Design 3 and key question is how much potency will be lost relative to Design 3). Design 5 (fluoro at C7 of IQ: obvious modification to block metabolism and loss of potency likely to be small). Designs 6/7 (naphthyridines: use electron-releasing substituent at C6 to counter HB basicity weakening effect of C7 aza on the nitrogen that accepts HB). Designs 8/9 (combine electron-withdrawing C6 substituent with fluoro at C7 with a view to achieving small increase in potency while protecting C7/C8 from metabolism). Submission notes for PET-UNK-f4e47ebd are relevant to current submission.
Other Notes:
Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P0157 A chain protein structure [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-11] Designs 1-9.