Submission Details
Molecule(s):
CC(F)(F)c1cc(Cl)cc(CC(=O)Nc2cncc3ccccc23)c1
CCC(F)(F)c1cc(Cl)cc(CC(=O)Nc2cncc3ccccc23)c1
PET-UNK-8c422e11-3
Duplicate of:
MIC-UNK-16ccb665-1
O=C(Cc1cc(Cl)cc(OC(F)F)c1)Nc1cncc2ccccc12
CC(F)(F)Oc1cc(Cl)cc(CC(=O)Nc2cncc3ccccc23)c1
Design Rationale:
This submission is derived from the PET-UNK-bb7ffe78 submission. Designs 1 and 3 of PET-UNK-bb7ffe78 have been difluorinated on the benzylic carbon of the alkyl substituent. This is expected to help protect the P2 phenyl from metabolism (protection may extend to the methylene that links the the P2 benzene ring to the amide carbonyl) but I would not anticipate gains in potency to result from this structural modification. Design 2 of PET-UNK-bb7ffe78 has been modified by substituting (1) H or (2) methyl for one of the fluorines of the CF3O substituent. These designs have been included for their potential to lead to increased potency.
Other Notes:
The PDB file contains (1) Protein structure from x10789 (2) TRY-UNI-2eddb1ff-7 ligand from x10789 (3) Designs 1-4 from current submission (design 3 is actually a re-submission of MIC-UNK-16ccb665-1 and labelled as such in the pdb file associated with this submission). Binding modes for previous and current designs given in pdb file have been energy-minimized (MMFF94S) using szybki (OpenEye). I would recommend awaiting assay results for the three designs (all of which have been ordered) of the PET-UNK-bb7ffe78 submission before committing to synthesis of the designs in the current submission.