Submission Details
Molecule(s):
CN1C[C@@H](c2cccc(Cl)c2)C(=O)N(c2cncc3ccccc23)C1=O
CCN1C[C@@H](c2cccc(Cl)c2)C(=O)N(c2cncc3ccccc23)C1=O
Cc1ccncc1N1C(=O)[C@H](c2cccc(Cl)c2)CN(C)C1=O
CCN1C[C@@H](c2cccc(Cl)c2)C(=O)N(c2cnccc2C)C1=O
CN1C[C@@H](c2cccc(Cl)c2)C(=O)N(c2cccnc2)C1=O
CCN1C[C@@H](c2cccc(Cl)c2)C(=O)N(c2cccnc2)C1=O
Design Rationale:
Structural variations of PET-UNK-abc197b8-1 (R enantiomer of VLA-UCB-1dbca3b4-18) dihydrouracil with combinations of P1 heterocycle (3x) and N-alkyl group (2x). Models built by editing existing model for PET-UNK-abc197b8-1 and energy-minimized using Szybki (MMFF94S) from OpenEye.
Other Notes:
I'm assuming that PET-UNK-abc197b8-1 and/or the racemate VLA-UCB-1dbca3b4-18 will have been evaluated before the synthesis of any of these is attempted. I would anticipate that the potency advantage for isoquinoline over pyridine will less for dihydrouracils than for the parent series (e.g. ADA-UCB-6c2cb422-1) on account of the carbonyl groups that flank the P1 substituent. The x10789 crystal structure (ligand: TRY-UNI-2eddb1ff-7) was used for modeling and the protein in the pdb file is from the energy-minimized complex with the first designed ligand. The x10789 crystallographic ligand is included in the pdb file as well as the 6 designs.