Submission Details
Molecule(s):
N#CC1(CS(=O)(=O)N2Cc3c(F)cc(Cl)cc3[C@H](C(=O)Nc3cncc4ccccc34)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ncc(Cl)cc3[C@H](C(=O)Nc3cncc4ccccc34)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3c(F)cc(Cl)cc3C(C(=O)Nc3cncc4ccccc34)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ncc(Cl)cc3C(C(=O)Nc3cncc4ccccc34)C2)CC1
Design Rationale:
The two designs in this submission address potential metabolism at the P2 aromatic ring using structural modifications (RAL-THA-2d450e86-14 | RAL-THA-2d450e86-30) of the 3-chlorobenzyl known to be well tolerated. Sulfonylation of dihydroisquinoline nitrogen will render the carbonyl more electron-withdrawing and would be expected reduce metabolism at the P2 aromatic ring (greater metabolic stability of ALP-POS-c56c1477-3 relative to MAT-POS-e194df51-1 would point to metabolism at P2 as an issue). The racemic forms for the two designs are included the submission.
Other Notes:
Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S), fixing the coordinates the oxygen and nitrogen of the amide. The PDB file associated with this submission contains the following: [1] P1788 A chain protein structure [2] P1788 A chain crystallographic ligand (MAT-POS-dc2604c4-1) [3-4] Binding modes predicted for Designs 1 and 2.