| STUDY |
A new class of substituted gamma-lactam compounds may hold promise for the treatment of the inflammatory autoimmune disease rheumatoid arthritis. These gamma-lactam compounds are highly selective inhibitors of the metalloprotease responsible for producing active tumor necrosis factor alpha (TNFalpha) a cytokine that plays a critical role in eliciting the body's inflammatory response and that is present in abnormally high levels in the joints of patients suffering from rheumatoid arthritis. In the absence of structural information about this metalloprotease, also known as TACE (Abbrev.) Authors used computer-aided drug design and the structure of a related enzyme to predict TACE inhibitors. The gamma-lactam hydroxamic acid compounds they came up with are extremely potent and highly selective inhibitors of TNFalpha production, and one in particular (shown) exhibits excellent oral bioavailability in both rats and dogs. A structurally related compound is in clinical trials for the treatment of rheumatoid arthritis.
|