Submission Details
Molecule(s):
CNC(=O)CN1Cc2ccc(Cl)cc2C2(CCN(c3cncc4ccccc34)C2)C1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCN(c4cncc5ccccc45)C3)C2)CC1
CNC(=O)CN1Cc2ccc(Cl)cc2C2(CC(=O)N(c3cncc4ccccc34)C2)C1
CNC(=O)CN1Cc2ccc(Cl)cc2C2(CCN(c3cncc4ccccc34)C2=O)C1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CC(=O)N(c4cncc5ccccc45)C3)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
CNC(=O)CN1CC2(CCN(c3cncc4ccccc34)C2)c2cc(Cl)ccc2C1=O
CNC(=O)CN1CC2(CCN(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
CNC(=O)CN1CC2(CC(=O)N(c3cncc4ccccc34)C2)c2cc(Cl)ccc2C1=O
Design Rationale:
Spiro succinimide VLA-UCB-50c39ae8-2, is usefully potent with the amide link conformationally restricted. The tetrahydroisoquinoline P2 series with N-glycine and N-sulfonamides have enhanced potency over the benzopyrans. The dihydroisoquinolones have improved metabolic stability and potency over the tetrahydroisoquinolines. Removal of one or both of the succinimide carbonyls may reduce solvation and therefore improve potency. Removal of both to give the spiro pyrollidine would be expected to improve the hydrogen bond basicity of the P1 isoquinoline. Reduction of the hydrogen bond count would be expected to give enhanced CNS penetration which is both a benefit (access to potential CNS SARS-CoV2 as a driver of long COVID) and a risk - increase risk of interacting with CNS tox targets.