Submission Details
Molecule(s):
N#CC1(CS(=O)(=O)N2Cc3c(F)cc(Cl)cc3C3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3cc(F)c(Cl)cc3C3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCN(c4cncc5ccccc45)C3=O)C2C(F)(F)F)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCN(c4cncc5ccccc45)C3=O)C2C(F)F)CC1
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:
Resubmitting racemic parts of submission: VLA-UNK-61877630 for better visibility on key designs.