Submission Details
Molecule(s):
CNC(=O)CN1CC2(CCN(c3cncc4ccccc34)C2=O)c2cc(Cl)cc(F)c2C1=O
CNC(=O)CN1CC2(CCN(c3cncc4ccccc34)C2=O)c2cc(Cl)c(F)cc2C1=O
CNC(=O)CN1CC2(CCN(c3cncc4ccccc34)C2=O)c2cc(F)cc(F)c2C1=O
CNC(=O)CN1C(=O)c2ccc(Cl)cc2C2(CCN(c3cncc4ccccc34)C2=O)C1C(F)(F)F
CNC(=O)CN1C(=O)c2ccc(Cl)cc2C2(CCN(c3cncc4ccccc34)C2=O)C1C(F)F
Design Rationale:
Transformations to increase the half-life based on published MMPs in "Strategy for Extending Half-life in Drug Design and Its Significance" (DOI: 10.1021/acsmedchemlett.8b00018) and "Why Decreasing Lipophilicity Alone Is Often Not a Reliable Strategy for Extending IV Half-life (DOI:10.1021/acsmedchemlett.8b00047). Add non-metabolically liable lipophilicity to net improve half-life (by improving vol. of distribution by a bigger margin than clearance). MMP for methylation on ring suggest a tiny boost in affinity.
Other Notes:
Resubmitting racemic parts of submission: VLA-UNK-61877630 for better visibility on key designs.