Submission Details
Molecule(s):
CNC(=O)CN1C(=O)c2ccc(Cl)cc2C(C(=O)Nc2cncc3ccccc23)C1C(F)(F)F
CNC(=O)CN1C(=O)c2ccc(Cl)cc2C(C(=O)Nc2cncc3ccccc23)C1C(F)F
CNC(=O)CN1C(=O)c2ccc(Cl)cc2[C@]2(CCN(c3cncc4ccccc34)C2=O)C1C(F)(F)F
CNC(=O)CN1C[C@@]2(CCN(c3cncc4ccccc34)C2=O)c2cc(Cl)cc(F)c2C1=O
CNC(=O)CN1C[C@@]2(CCN(c3cncc4ccccc34)C2=O)c2cc(Cl)c(F)cc2C1=O
CNC(=O)CN1C(=O)c2ccc(Cl)cc2[C@]2(CCN(c3cncc4ccccc34)C2=O)C1C(F)F
N#CC1(CS(=O)(=O)N2Cc3c(F)cc(Cl)cc3[C@]3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3cc(F)c(Cl)cc3[C@]3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@]3(CCN(c4cncc5ccccc45)C3=O)C2C(F)(F)F)CC1
O=C1N(c2cncc3ccccc23)CC[C@@]12CN(S(=O)(=O)CC1(C(F)(F)F)CC1)Cc1ccc(Cl)cc12
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).
Other Notes:
The last one is an enantiomer of EDJ-MED-5cd3920d-6