Submission Details
Molecule(s):
Cn1ncc2cncc(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)c21
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@H](C(=O)Nc3cncc4cn[nH]c34)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@H](C(=O)Nc3cncc4sccc34)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@H](C(=O)Nc3cncc4occc34)C2)CC1
COc1cc2c(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)cncc2cc1F
CN(C)c1cc2c(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)cncc2cn1
CN(C)c1cc2c(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)cncc2cn1
COc1ccc2cncc(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)c2c1
CN(C)c1ccc2cncc(NC(=O)[C@@H]3CN(S(=O)(=O)CC4(C#N)CC4)Cc4ccc(Cl)cc43)c2c1
Design Rationale:
The designs in this submission combine the tetrahydroisoquinoline substituent of MAT-POS-dc2604c4-1 with 9 variations/substitutions of the parent isoquinoline (IQ) that are intended to address potential metabolism at C7/C8 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). Designs 5/6 (combine electron-releasing substituent at C6 with fluoro at C7 with a view to achieving small increase in potency while protecting C7/C8 from metabolism). Designs 7/8 (naphthyridines: use electron-releasing substituent at C6 to counter HB basicity weakening effect of C7 aza on the nitrogen that accepts HB). Designs 9/10 (electron-releasing substituents at C6; wouldn’t be expected to affect metabolism significantly but this is a convenient place to submit the structures). 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] Binding mode predicted for EDJ-MED-be9e6f63-1 [4-13] Binding modes for Designs 1-10.