Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3cccc(C)c23)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(=N\CC(F)(F)F)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(=N\CC(F)F)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(F)=C/c2cncc3ccccc23)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(=N\CC(F)(F)F)Nc2cncc3cccc(C)c23)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(=N\CC(F)F)Nc2cncc3cccc(C)c23)CCOc2ccc(Cl)cc21
CO[C@@]1(C(=S)Nc2cncc3cccc(C)c23)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(Cc2cncc3ccccc23)=N\CC(F)(F)F)CCOc2ccc(Cl)cc21
CO[C@@]1(/C(Cc2cncc3ccccc23)=N\CC(F)F)CCOc2ccc(Cl)cc21
Design Rationale:
If amide metabolism is problematic and reason behind short T1/2 of lead compound; can sterics be used to slow down amide bond cleavage, e.g. alkyl group near amide bond? how about amide bioisosteres as in (lower pKa) amidines? See, review: https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00530
Other Notes:
Have you also considered formulation or a prodrug strategy? Would cyclodextrin improve stability? I'm assuming a thioamide would be auseful intermeidate so might as well test this as well?