Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(Cl)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(S(C)(=O)=O)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(NS(C)(=O)=O)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(Cl)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(S(C)(=O)=O)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(NS(C)(=O)=O)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(F)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(Cl)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(S(C)(=O)=O)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(NS(C)(=O)=O)ccc23)CNS(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(F)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(Cl)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(S(C)(=O)=O)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(NS(C)(=O)=O)ccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
Using methoxy as the configurational lock may be beneficial (methoxy-locked chromane is about 3-fold more potent than methyl-locked analog and alignment of C-O bond with amide NH may draw some of the latter’s sting). The instability of methoxy-locked dihydroisoquinolones is likely to be due to the planarity of the amide (the cyclic sulfonamide ring is geometrically more similar to a chromane but more rigid on account of the strong conformational preference of the sulfonamide). Each of the 8 cyclic sulfonamides in this submission incorporates the methoxy configuration lock and the designs have been generated combinatorially (N with/without methyl substituent x 4 substituents at C7 of the P1 isoquinoline that are currently of interest for addressing metabolism). The racemate for each design has been included in the submission.
Other Notes:
Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3-10] Binding modes predicted for Binding modes predicted for Designs 1-8.