ABSTRACT
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , ADAM Proteins , ADAM17 Protein , Administration, Oral , Animals , Biological Assay , Cartilage/drug effects , Cartilage/enzymology , Cattle , Dialysis , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 13 , Metalloendopeptidases/antagonists & inhibitors , Mice , Osteoarthritis/drug therapy , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.