Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CCOc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(C#N)ccc23)CCOc2ccc(Cl)cc21
CN(C)S(=O)(=O)CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
NS(=O)(=O)CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
C=CS(=O)(=O)CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
Design Rationale:
Two C7-substituted analogs of PET-UNK-29afea89-2 intended to address potential metabolic instability of isoquinoline. Three analogs of PET-UNK-4880b143-1 to map SAR (including a vinyl sulfone to target catalytic cysteine).
Other Notes:
Design 1 moves the C6-fluoro substituent of EDJ-MED-611d11e7-4 to C7 and I do not anticipate that this transformation will result in significant loss of potency. Design 2 is more speculative but likely to provide more protection against metabolic turnover (and more likely to compromise potency). PET-UNK-4880b143-1 is currently being synthesized and it could be an idea to wait until assay results are available for that compound before committing to synthesis of Designs 3-5. The A-chain of the P0157 crystal structure (ligand: PET-UNK-29afea89-2) was used for modeling and the side chain of N142 has been rotated by 180 degrees to assess potential hydrogen bond donation to the sulfonyl oxygens of the first two designs. The pdb file associated with this submission includes (1) Protein structure from energy-minimized complex with PET-UNK-4880b143-1 (2) Crystallographic ligand (PET-UNK-29afea89-2) from A-chain of P0157 (3) Crystallographic ligand (the fragment AAR-POS-d2a4d1df-1) from aligned x0072 crystal structure (4) Updated binding mode generated for PET-UNK-4880b143-1 (5) Binding modes generated for the five designs in current submission.