Abstract
Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1' pockets and the known advantageous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity.
MeSH terms
-
ADAM Proteins / antagonists & inhibitors*
-
ADAM17 Protein
-
Drug Design
-
Enzyme Inhibitors* / chemical synthesis
-
Enzyme Inhibitors* / chemistry
-
Enzyme Inhibitors* / pharmacology
-
Hydroxamic Acids* / chemical synthesis
-
Hydroxamic Acids* / chemistry
-
Hydroxamic Acids* / pharmacology
-
Metalloproteases / antagonists & inhibitors*
-
Molecular Structure
-
Structure-Activity Relationship
-
Sulfonamides* / chemical synthesis
-
Sulfonamides* / chemistry
-
Sulfonamides* / pharmacology
Substances
-
Enzyme Inhibitors
-
Hydroxamic Acids
-
Sulfonamides
-
Metalloproteases
-
ADAM Proteins
-
ADAM17 Protein