Submission Details

Molecule(s):
O=C(CN1CC(C(=O)Nc2cncc3ccc(F)cc23)c2ccccc2C1=O)NC1COC1

EDG-MED-9fc99cca-1

O=C(CN1CC(C(=O)Nc2cncc3ccc(F)cc23)c2ccccc2C1=O)NC1COC1

O=C(CN1CC(C(=O)Nc2cncc3ccc(Cl)cc23)c2ccccc2C1=O)NC1COC1

EDG-MED-9fc99cca-2

O=C(CN1CC(C(=O)Nc2cncc3ccc(Cl)cc23)c2ccccc2C1=O)NC1COC1

CNC(=O)C(C)(C)N1CC(C(=O)Nc2cncc3cc(S(C)(=O)=O)ccc23)c2ccccc2C1=O

EDG-MED-9fc99cca-3

CNC(=O)C(C)(C)N1CC(C(=O)Nc2cncc3cc(S(C)(=O)=O)ccc23)c2ccccc2C1=O

CNC(=O)C1(N2CC(C(=O)Nc3cncc4cc(S(C)(=O)=O)ccc34)c3ccccc3C2=O)CC1

EDG-MED-9fc99cca-4

CNC(=O)C1(N2CC(C(=O)Nc3cncc4cc(S(C)(=O)=O)ccc34)c3ccccc3C2=O)CC1


Design Rationale:

Combine tetrahydroisoquinolone glycine amide potency with metabolism reducing substitution s on NH and isoquinoline keeping logP in bounds to avoid permeability issues. Note gem di methyl and cyclopropyl amides would be expected to show different pofenies due to significantly different conformational preference.

Discussion: