Abstract
Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.
MeSH terms
-
ADAM Proteins / antagonists & inhibitors*
-
ADAM17 Protein
-
Administration, Oral
-
Alkanes / chemical synthesis
-
Alkanes / chemistry*
-
Alkanes / pharmacokinetics
-
Alkanes / pharmacology
-
Animals
-
Biological Availability
-
Caco-2 Cells
-
Humans
-
Hydroxamic Acids / chemical synthesis
-
Hydroxamic Acids / chemistry*
-
Hydroxamic Acids / pharmacokinetics
-
Hydroxamic Acids / pharmacology*
-
Matrix Metalloproteinase Inhibitors
-
Matrix Metalloproteinases / metabolism
-
Models, Molecular
-
Protease Inhibitors / chemical synthesis
-
Protease Inhibitors / chemistry*
-
Protease Inhibitors / pharmacokinetics
-
Protease Inhibitors / pharmacology*
-
Rats
-
Rats, Sprague-Dawley
-
Spiro Compounds / chemical synthesis
-
Spiro Compounds / chemistry*
-
Spiro Compounds / pharmacokinetics
-
Spiro Compounds / pharmacology
Substances
-
Alkanes
-
Hydroxamic Acids
-
Matrix Metalloproteinase Inhibitors
-
Protease Inhibitors
-
Spiro Compounds
-
ADAM Proteins
-
Matrix Metalloproteinases
-
ADAM17 Protein
-
ADAM17 protein, human
-
Adam17 protein, rat
-
nonane