Submission Details
Molecule(s):
CS(=O)(=O)Nc1ccc2cncc(NC(=O)[C@@H]3CS(=O)(=O)Cc4ccc(Cl)cc43)c2c1
CN(c1ccc2cncc(NC(=O)[C@@H]3CS(=O)(=O)Cc4ccc(Cl)cc43)c2c1)S(C)(=O)=O
CS(=O)(=O)Nc1cc2c(NC(=O)[C@@H]3CS(=O)(=O)Cc4ccc(Cl)cc43)cncc2cc1F
CN(c1cc2c(NC(=O)[C@@H]3CS(=O)(=O)Cc4ccc(Cl)cc43)cncc2cc1F)S(C)(=O)=O
CO[C@@]1(C(=O)Nc2cncc3ccc(NS(C)(=O)=O)cc23)CS(=O)(=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(N(C)S(C)(=O)=O)cc23)CS(=O)(=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(NS(C)(=O)=O)cc23)CS(=O)(=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(N(C)S(C)(=O)=O)cc23)CS(=O)(=O)Cc2ccc(Cl)cc21
Design Rationale:
The designs in this submission are intended to address metabolism of the P1 isoquinoline while minimizing loss of potency relative to the parent compound PET-UNK-1b92fa34-1. The designs combine the alternative cyclic sulfone P2 group of PET-UNK-1b92fa34-1 with the 6-methanesulfonamido-isoquinoline (potential for metabolic protection with minimal loss of potency) from EDG-MED-10fcb19e-1 and EDJ-MED-d9f3798e-3. The N-methyl (sulfonamide), 7-fluoro and methoxy (configurational lock) substitutions are performed combinatorially on Design 1 to give a total of 8 designs. The design notes for the PET-UNK-a7639856 submission are relevant to the current submission and an example of the alternative cyclic sulfone (MAT-POS-1a13cd81) has been ordered for synthesis.
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) [3-10] Designs 1-8.