Submission Details
Molecule(s):
CN(C)c1ccc2cncc(NC(=O)Cc3cccc(Cl)c3)c2c1
CN(C)c1cc2c(NC(=O)Cc3cccc(Cl)c3)cncc2cc1F
CN(C)c1cc2c(NC(=O)Cc3cccc(Cl)c3)cncc2cn1
Design Rationale:
The designs in this submission use the electron-releasing dimethylamino group to increase the hydrogen bond basicity of the P1 aromatic nitrogen that accepts a hydrogen bond from the protein. Protonation of Design 1 is a potential concern (pKa of 6-aminoisoquinoline is 7.2; see https://doi.org/10.1021/jo00972a031 ) although the C4-amido substituent may be sufficiently electron-withdrawing to counteract this tendency. Design 2 places a fluorine at C7 (potential to protect against metabolism) next to the electron-releasing dimethylamino substituent at C6 (which has the potential to counteract the slight potency-weakening effect of the C7 fluoro) and the P1 group can be seen as analogous to the P1 group of PET-UNK-b38839dc-1. Design 3 substitutes C7 of Design 1 with nitrogen (potential to protect against metabolism) and the electron-releasing dimethylamino substituent at C6 has the potential to counteract the potency-weakening effect that has been observed for 7-aza substitution. The P1 group of Design 3 can be regarded as analogous to the P1 groups of the methoxynaphthyridine PET-UNK-f4e47ebd-1 and the pyrazolopyridine RUB-POS-1325a9ea-14.
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) [3-5] Binding modes predicted for Designs 1-3.